Enhanced immunity against cancer -
Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance.
Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies.
Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
During cancer evolution, accumulating point mutations and structural alterations drive malignant transformation and contribute to the immunogenicity of cancer cells [ 1 ].
Tumor antigens expressed by mutated genes could be recognized by host immunity as non-self and initiate immune elimination [ 2 ]. In immune-mediated elimination, innate immunity cooperates with adaptive immunity to orchestrate a cascade multi-step process, which begins with tumor antigen capture and ends with immune killing [ 3 , 4 , 5 , 6 ].
Innate immunity serves as the first front line of host defense, consisting of physical and chemical barriers and various types of immune cells with pattern-recognition receptors PRRs. Innate immune components, involving dendritic cells DCs , macrophages, monocytes, neutrophils, eosinophils, basophils, mast cells, natural killer NK cells, natural killer T NKT cells, γδ T cells, mucosa-associated invariant T MAIT cells, retard tumor growth mainly by nonspecifically killing malignant cells or mobilizing adaptive immune response [ 7 ].
In contrast with the innate arm, the adaptive arm of host immunity specifically eradicates cancer cells by T and B cells [ 8 ]. Ideally, all transformed cells are recognized and eliminated by host immunity.
However, cancer is a heterogeneous disease, and a large scale of genetic and epigenetic alterations are unevenly distributed in several parallel subclones [ 9 , 10 , 11 ]. Under the selective pressure of adaptive immunity, tumor subclones with weak immunogenicity become the predominant subclones that escape immune-mediated tumor clearance [ 12 ].
The poor immunogenicity, coupled with multiple immunosuppressive factors such as immune checkpoint pathways, metabolite reprogramming, and dysregulated cytokine repertoire, support selected subclones to develop into clinically apparent lesions [ 13 , 14 , 15 , 16 , 17 , 18 ].
Besides, immunosuppressive cell populations in the tumor microenvironment TME , including tumor-associated macrophages TAMs , regulatory T Treg cells, regulatory B Breg cells, myeloid-derived suppressor cells MDSCs , tumor-associated neutrophils TANs , and cancer-associated fibroblasts CAFs , also promote immune evasion and cancer progression [ 19 , 20 , 21 , 22 , 23 ].
Antitumor immunotherapies, including immune checkpoint blockade [ 24 ] and adoptive cell transfer [ 25 , 26 , 27 ], have been widely validated and clinically approved for various cancers. These strategies aim to eradicate cancer cells by enabling T cell-mediated antitumor responses.
Immune checkpoint molecules are commonly upregulated in the TME, which hamper T cell activation by counteracting T cell receptor TCR signaling or attenuating the costimulatory pathway [ 28 , 29 , 30 ].
Meanwhile, adoptive cell transfer strategies, mainly chimeric antigen receptor CAR -T cell therapy, make a breakthrough in hematological malignancies [ 33 , 34 ]. CAR-T cells are prepared by transducing genetically engineered receptors into autologous T cells [ 35 ].
These engineered TCRs contain extracellular domains recognizing tumor antigens and intracellular domains mimicking TCR activation signaling [ 36 , 37 ]. At the present stage, six CAR-T cell products have been clinically approved: Yescarta anti-CD19 , Kymriah anti-CD19 , Tecartus anti-CD19 , Breyanzi anti-CD19 , Abecma anti-BCMA , and Carvykti anti-BCMA for B cell malignancies and multiple myeloma [ 38 , 39 , 40 , 41 ].
Also, DC-targeted adoptive cell transfer strategies have made substantial headway. Provenge, autologous DC loaded with the fusion protein of granulocyte—macrophage colony-stimulating factor and prostatic acid phosphatase, has been approved for prostate cancer [ 42 ].
Although these immunotherapies have achieved tremendous success in advanced cancers, some thorny issues remain to be resolved, including the unsatisfactory response rate and lack of accurate predictors.
It was estimated that Besides, CAR-T cell therapy indications are limited to hematologic malignancies, without significant antitumor activity in solid tumors [ 44 , 45 , 46 , 47 ].
Generally, most clinically approved immunotherapies are T cell-centered. However, the effector functions of T cells are non-autonomous. The initiation and sustainability of T cell response and the maintenance of T cell memory depend on innate immunity [ 48 ].
Innate immunity detects, captures, and processes cancer antigens and then triggers adaptive immunity. At the same time, innate immune cells directly eradicate tumors by mounting their effector responses, such as the cytotoxicity of NK cells and the phagocytosis of macrophages [ 48 ].
Besides, due to the expression of Fc receptor FcR on macrophages and NK cells, innate immunity could participate in adaptive immunity by launching antibody-dependent cell cytotoxicity and phagocytosis ADCC and ADCP [ 49 ].
As the essential role of the innate immune arm in the onset, propagation, and maintenance of the cancer-immunity cycle, it is rationale to harness innate response to improve the current immunotherapy performance and relieve treatment resistance.
In this work, we review the roles of innate immune components in antitumor immunity and summarize the advances in innate immunity-targeted immunotherapies. DCs are a heterogeneous group of myeloid-derived populations.
According to the developmental origin, DCs are commonly classified into several subsets: conventional DC including cDC1 and cDC2 , plasmacytoid DC pDC , monocyte-derived DC MoDC , and tumor-infiltrating DC3 [ 50 ]. Among these subsets, cDC1 is functionally specialized in the cross-presentation of cancer antigens [ 51 , 52 ], while pDC is the specialized producer of IFN-I [ 53 ].
Besides, based on tissue-specific compartmentalization, DCs could be classified as migratory DC migDC, trafficking from peripheral tissues to draining lymph nodes and resident DC resDC, residing in peripheral lymphoid organs.
Notably, the omics technique, especially single-cell RNA sequencing, provides a high-resolution landscape of DC differentiation and ontogeny [ 54 ]. To trigger and maintain robust antitumor response, DCs orchestrate a cascade of events: antigen capture and process, trafficking to tumor-associated draining lymph nodes tdLNs , priming naïve T cells, recruiting primed T cells into the TME by secreting chemokines, and interacting with effector T cells in the TME [ 55 ].
The presence and accumulation of DCs are the prerequisites of innate immune sensing. The recruitment and expansion of DC in the TME are dependent on several cytokines and chemokines, such as NK cell-derived FLT3L [ 56 ], XCL1, CCL5 [ 57 ], as well as tumor-derived CCL4 [ 58 ].
In the presence of damage-associated molecular patterns DAMPs from stressed or injured cancer cells, these immature DCs are activated by various PRR pathways [ 59 ].
Additionally, chemotherapy and radiotherapy could promote DC maturation by inducing the immunogenic cell death ICD of cancer cells [ 60 ]. DAMPs released during ICD stimulate DC maturation and improve DC functions: adenosine triphosphate ATP facilitating DC recruitment and activation, calreticulin CRT enhancing cancer antigen engulfment, and high-mobility group box 1 HMGB1 improving antigen presentation of DCs [ 60 ].
DC-targeted cancer therapies. a The maturation of DCs. Besides, In the presence of damage-associated molecular patterns from stressed or injured cancer cells, these immature DCs are activated by various PRR pathways. Additionally, chemotherapy and radiotherapy could promote DC maturation by inducing the ICD of cancer cells.
DAMPs released during ICD stimulate DC maturation and improve DC functions: ATP facilitates DC recruitment and activation, CRT enhances cancer antigen engulfment, and HMGB1 improves antigen presentation of DCs.
b DC-targeted cancer therapies. DC-targeted strategies mainly consist of agonists for DC differentiation, expansion, and activation, blockade of immunoinhibitory signals, and DC vaccines. Abbreviations: DC, dendritic cell; ICD, immunogenic cell death; ATP, adenosine triphosphate; CRT, calreticulin; HMGB1, high-mobility group box 1.
Adapted from Yi et al. Once upon cancer antigen capture, DCs undergo maturation with the licensing stimuli such as IFN-I. In this process, DCs alter their morphology, upregulate costimulatory molecules such as CD40, CD80, and CD86, enhance antigen presentation capability, and secret proinflammatory cytokines [ 63 ].
Apart from tdLNs, DCs could continue interacting with T cells in the TME to support cancer-specific immunity. Tumor-infiltrating cDC1 promotes T cell infiltration by secreting CXCL9 and CXCL10 ligands of CXCR3 to guide T cell homing [ 67 ].
Recent studies demonstrate a positive feedback loop between cDC1s and T cells. The functions of DCs are disturbed by various immunosuppressive factors in the TME, hampering immune surveillance and supporting tumor progression [ 71 ]. Some tumor and stroma-derived cytokines regulate the survival, differentiation, maturation, and antigen presentation of DCs.
For example, transforming growth factor-β TGF-β is a crucial component in maintaining host immune homeostasis [ 72 ]. Deleting Tgfbr2 in DCs by CD11c-Cre murine models leads to multiorgan inflammation [ 73 ].
On the one hand, TGF-β inhibits the antigen-presentation of DCs by downregulating MHC-II expression [ 74 ]. Also, the TGF-β-inhibitor of differentiation 1 ID1 axis induces DC differentiation toward an immunosuppressive myeloid cell phenotype [ 75 ]. In murine melanoma and breast cancer models, activated TGF-β signaling increases enzyme indoleamine 2,3-dioxygenase IDO in pDCs and CCL22 in myeloid DCs, promoting Treg infiltration as well as immune escape [ 76 ].
On the other hand, these tolerogenic DCs contribute to cancer immune evasion by TGF-β secretion. Tumor cells educate DCs to generate TGF-β, which in turn facilitates Treg differentiation [ 77 ]. Along with TGF-β, other immunoinhibitory molecules also limit the functions of DCs.
IL drives the transformation of immature DCs towards the tolerogenic phenotype [ 78 ]. IL-6 undermines DC maturation by STAT3-mediated downregulation of MHC-II and CCR7 [ 79 ]. PGE2 alone could disturb NK cell-stimulated cDC1 recruitment by suppressing NK cell survival and chemokine receptor expression of cDC1 [ 57 ].
Vascular endothelial-derived growth factor VEGF is identified as another cytokine hampering the differentiation and antigen presentation of DCs [ 83 , 84 , 85 ]. Increased VEGF is associated with decreased circulating and tumor-infiltrating DCs [ 86 ]. Some tumor-derived metabolites, such as oxysterols and lactic acid, restrain the CCR7-mediated migration and antigen presentation capability of DCs [ 87 , 88 ].
Further investigations showed the activation of lactate receptor GPR81 specifically downregulated MHC-II expression [ 89 ]. Generally, the functions of DCs are dampened, and antigen presentation machinery is disorganized in the TME [ 90 ]. Therefore, reinvigorating DC from abnormal status is feasible to boost antitumor immunity and overcome immunotherapy resistance [ 91 , 92 ].
As the core component bridging innate immunity and adaptive immunity, DC is a valuable target for immunotherapy, especially for patients resistant to T cell-based therapies. At present, DC-targeted strategies mainly consist of agonists for DC differentiation, expansion, and activation, blockade of immunoinhibitory signals, and DC vaccines Fig.
cGAS recognizes cytoplasmic double-stranded DNA and then catalyzes the formation of secondary messenger cyclic GMP-AMP cGAMP.
At the same time, STING-dependent NF-κB activation enables DCs to generate proinflammatory cytokines. Notably, in some tumor-associated myeloid cells, STING-dependent NF-κB signaling could also be initialized by inhibitor of kB kinase ε IKK-ε in a TBK1-independent manner [ 96 ].
Based on the immunostimulatory effects of STING-dependent IFN-I production, pharmacological activation of STING by intratumorally injecting cGAMP retards tumor growth in multiple murine colon carcinoma and melanoma models [ 97 , 98 , 99 , , ]. However, the applications of cGAMP and synthetic cyclic dinucleotides CDNs are limited by poor bioavailability and intratumoral delivery [ ].
Relatively, non-CDN small-molecule STING agonists overcome these shortcomings that could be systemically delivered. Despite the failure of DMXAA [ ], some novel STING agonists, such as di-ABZI, MSA-2, and manganese, exhibit potent antitumor activity in murine tumor models, which are undergoing clinical evaluations Table 2 [ , , , , ].
These STING agonists effectively upregulate costimulatory molecules e. As a result, STING agonist administration enhances the expression of IFN-β and other proinflammatory cytokines e. Besides, some STING agonists, such as manganese, could strengthen NK cell activation and NK cell-mediated cytotoxicity in the TME [ ].
STING agonists are a promising strategy for cancer immunotherapy, mobilizing the innate defensive sensor for immunological surveillance and promoting cancer-specific T cell priming.
Up to now, more than ten functional TLRs TLR have been identified in humans [ ]. TLR3 agonist such as Poly I:C enhances cDC1 maturation and cytokine production such as IL and IFN-I [ ].
Additionally, TLR8 agonist, such as Motolimod, promotes cDC1 maturation, with encouraging antitumor activity and tolerable toxicity profiles in squamous cell head and neck cancer [ , , ].
Moreover, TLR7 and TLR9 are widely explored due to their capability to induce IFN-I generation in pDCs. The immunostimulatory effects and antitumor activity of TLR7 agonists such as Imiquimod have been confirmed in various types of cancer [ , , , ].
TLR9 agonists also promote cytokine production and pDC maturation [ , ]. Also, other novel agents such as granulocyte macrophage-colony stimulating factor GM-CSF , Flt3L agonist, and RIG-I agonist improve DC-mediated T cell response by expanding DC population, promoting DC activation or phagocytic potential [ , , , ].
In some murine tumor models, the antitumor activity of agonistic CD40 antibodies is T cell-dependent [ , , ]. However, some current studies showed that CD40 activation-mediated tumor regression was independent of T cells. On the contrary, agonistic CD40 antibodies activate macrophages also highly expressing CD40 , causing stroma depletion and tumor regressions [ ].
To date, multiple CDtargeted monoclonal antibodies have been developed and tested in clinical trials [ ]. Generally, agonistic CD40 antibodies have a minimal response rate in cancer patients, except for selicrelumab [ ]. For most types of cancers with low immunogenicity, it is hard to effectively destroy tumors by agonistic CD40 antibody monotherapy.
Combination therapies with chemotherapy, radiotherapy, or other immunotherapies might be worth exploring in the future [ ]. As mentioned above, various immunosuppressive factors like TGF-β, IL, IDO, PGE2, and VEGF hamper the functions of DCs, hindering immune surveillance and promoting tumor advancement [ 93 , ].
Therefore, neutralizing these immunoinhibitory factors enhances the recruitment, survival, activation, and antigen presentation capability of DCs [ ]. Anti-VEGF antibodies improve the functions of DCs of spleen and lymph node, synergizing with peptide-pulsed DCs to prolong the survival of tumor-bearing mice [ ].
In a phase 1 study of VEGF-Trap, VEGF inhibition significantly increased the ratio of mature DCs, without alterations in populations of total DCs [ ].
Besides, in the MMTV-PyMT tumor model, blocking IL signaling by anti-IL receptor antibody enhanced treatment response to carboplatin and paclitaxel.
Also, neutralizing TGF-β by conventional or bispecific antibodies increases the number of functional DCs in the TME [ , , ]. Furthermore, IDO, functioning as an intracellular enzyme within the cytosol, transforms tryptophan into kynurenine.
This conversion disrupts the activities of cytotoxic T cells, elevates the presence of Tregs and TAMs, and impedes the maturation of DCs [ , , ]. Consequently, IDO contributes to rendering the TME more immunosuppressive, facilitating cancer escape from immune surveillance.
The application of anti-IDO siRNA therapy enhances cytokine production and the antigen presentation capabilities of DCs [ ]. Tumor vaccines that incorporate IDO inhibitors effectively enhance the uptake of tumor antigens and the maturation of DCs, ultimately inducing a robust tumor-specific T-cell response [ ].
Currently, numerous clinical trials are underway to assess the effectiveness of immunotherapies involving IDO inhibitors [ ]. Recent data demonstrate that PD-L1 on DCs dampens T cell activation and antitumor immune response.
PD-L1 blockade enhances de novo T cell priming in tdLNs and reactivates dysfunctional T cells in the TME [ ]. The antitumor activity of anti-PD-L1 therapy is more dependent on the renaissance of dysfunctional T cells inside tumors rather than newly activated T cell response in tdLNs [ ].
Moreover, DCs could simultaneously overexpress PD-1, PD-L1, and CD80 [ , ]. However, for patients with cancers, the expression level of PD-L1 is significantly higher than CD80 on tumor-associated and peripheral DCs [ ]. Apart from PD-L1, T-cell immunoglobulin and mucin domain 3 TIM-3 expressed on tumor-infiltrating DCs suppresses HMGB1-mediated activation of the innate sensing system [ ].
Further explorations reveal that TIM-3 limits HMGB1-dependent DNA uptake, while TIM-3 blockade promotes the activation of the cGAS-STING pathway and CXCL9 expression of cDC1 [ ]. The therapeutic potential of TIM-3 blockade is currently being evaluated in multiple types of cancers.
The administration of cancer antigens, which could be captured and presented by endogenous DCs, is a promising immunotherapy approach [ ].
These cancer antigen vaccines contain synthetic peptides, recombinant cancer antigen-expressing viruses, or tumor lysates [ 55 , ]. Fuelled by next-generation sequencing and prediction algorithms in silico, the identification of neoantigens increases the specificity of cancer antigen vaccines [ , , ].
Considering that antigen presentation by DCs is the cornerstone for cancer antigen vaccines, antigens and adjuvants are usually encapsulated in degradable biomaterial or nanoparticles [ , ]. To date, YS-ON rabies virus-based vaccine has been approved for pancreatic cancer and hepatocellular carcinoma in the US [ ].
Currently, advances have been made in targeted delivery to specific DC subsets [ ]. DEC, langerin, and CLEC9A are commonly used to target cDC1s. In vitro experiments confirm that the fusion protein of anti-DEC single-chain fragment variable and peptides of cancer antigen MAGE-A3 is presented more efficiently than direct peptide pulse [ ].
In addition to cancer antigen vaccines, the application of DC vaccines is extensively explored as well Table 3 [ ].
Such vaccines consist of manipulated autologous DCs isolated from cancer patients and expanded in vitro [ ]. cDC precursors or monocyte-derived DCs are loaded with cancer antigens, activated with cytokine cocktails, and then reinfused into patients [ ].
In various types of cancers, including non-small cell lung cancer NSCLC , ovarian cancer, prostate cancer, melanoma, renal cell carcinoma, and glioblastoma, DC vaccines exhibit potent antitumor activity with a manageable safety profile [ , , , , , , , , , , ].
At present, the DC vaccine sipuleucel-T consisting of autologous DCs pulsed with the recombinant fusion protein containing GM-CSF and prostatic acid phosphatase has been approved for prostate cancer [ ].
However, immunosuppressive TME is a great obstacle to DC vaccination. Thus, the combination of DC vaccination with other therapies, such as immune checkpoint inhibitors, appears ideal for fostering de novo cancer-specific T-cell response [ ].
When DCs encounter foreign stimuli, they undergo a mature process, with the upregulation of costimulatory molecules, MHC, and CCR7. Theoretically, CCL19 or CCL21 therapy could potentiate antitumor immunity by improving the trafficking of cytotoxic T cells and DCs.
In multiple murine tumor models, intratumoral injection of CCL19 or CCL21 increases the numbers of tumor-infiltrating DCs and T cells, retards tumor growth, and prolongs the survival of tumor-bearing mice [ , , , , ].
Besides, inducing tumor cells to overexpress CCL19 or CCL21 by transfection also enhances the functions of DCs and tumor control [ , , , ]. Also, autologous DCs engineered to overexpress CCR7 exhibit stronger migration capability and antitumor properties in murine tumors [ ].
Besides immune response, CCR7 signaling also contributes to tumor progression, especially metastasis to the lymph nodes [ ]. As a result, approaches inhibiting lymph node metastasis through CCR7 antagonism might unintentionally hinder the immune response to cancer.
Besides, IL is a proinflammatory cytokine that activates both the innate and adaptive arms of the host immune system. In preclinical investigations, recombinant IL has demonstrated strong antitumor effects [ ]. It has been observed that the success of anti-PD-1 therapy relies on the presence of ILproducing DCs [ 70 ].
To address the challenges associated with the toxicity of systemic IL administration, various localized delivery methods for IL have been developed. These approaches include immunocytokine fusion, cell-based delivery, nucleic acid-based delivery, and virus-based delivery [ , , , ].
Clinical studies have confirmed the safety of intratumoral injections involving an adenoviral vector encoding IL or DCs transfected with an adenovirus encoding IL [ , ].
Additionally, virotherapy through the intratumoral injection of a Semliki Forest virus encoding IL SFV-IL has been shown to induce an inflammatory response and synergize effectively with anti-PD-1 therapy in tumor models [ ].
Furthermore, SFV-IL has been found to enhance the therapeutic effects of a BB agonist antibody [ ]. Together, the outcomes of localized IL immunotherapies, particularly in preclinical studies, have shown significant potential, meriting further investigation in clinical studies.
Macrophages are a heterogeneous population of cells with high plasticity, showing diverse phenotypes under different stimuli [ ]. Historically, macrophages are classified into two phenotypes, commonly referred to as M1 classically activation, stimulated by IFN-γ and TLR ligands and M2 alternatively activation, stimulated by IL-4 and IL [ ].
M1 phenotype contributes to macrophage-mediated inflammatory tissue injury and tumor cell clearance, while M2 phenotype participates in damage repair and remodeling, as well as defense against parasites [ ]. In the process of inflammation, the activation and polarization of macrophages are dynamically changed: M1 cells in triggering and propagating immune response, M2 or M2-like populations in inflammation resolution, or smouldering chronic inflammation [ , , ].
However, with the development of omics technology, more and more novel macrophage subsets have been identified, and mixed expression of M1 and M2 biomarkers is also observed in tumor-infiltrating macrophages [ , , , ].
It is realized that the M1-M2 classification system is too simplistic to present complex phenotypes of macrophages. Tumor-infiltrating macrophage termed TAM is an important player in antitumor immune response and cancer progression [ ]. Although some studies have opposite results [ ], high infiltration of TAM is generally considered a risk factor in most preclinical and clinical studies [ ].
Notably, signals regulating the polarization and education of TAMs change in different tumors and even in different stages or spatial locations of the same tumor, leading to various phenotypes of TAMs [ , , ]. Therefore, TAM subsets should be preciously redefined to elaborate on the distinct roles of TAMs under specific circumstances.
Macrophages are recruited and educated by multiple factors in the TME, including colony-stimulating factor-1 CSF1 , GM-CSF, TGF-β, IL-1, IL-4, CCL2, CCL5, immune complexes, complement, histamine, tumor-derived non-coding RNAs [ , , , , ].
Besides, increased TNF-α and IL-1β in the TME could induce IL-8 expression, which recruits immunosuppressive myeloid leukocytes including macrophages and predicts poor outcomes in patients treated with immune checkpoint inhibitors [ , ].
As a result, TAMs are commonly set in the protumor M2-like phenotype [ ]. It has been validated that TAMs have substantial influences on tumor initiation and progression, especially by enhancing immune escape [ , , , , , ].
TAM-derived soluble molecules such as IL, IL, TGF-β, IDO, PGE2, and arginase 1 ARG1 directly suppress the functions of tumor-infiltrating T and NK cells Fig. Besides, autocrine IL and TNF-α stimulate PD-L1 upregulation on TAMs [ ]. Also, TAMs directly suppress the antitumor immune response by recruiting Tregs and supporting their differentiation [ ].
Chemokines produced by TAMs, including CCL5, CCL20, and CCL22, recruit Treg into TME, while TGF-β and IL induce Treg differentiation [ , ].
The protumor activities of TAMs and TAM-targeted cancer therapies. a The protumor properties of TAMs. TAMs are commonly set in the protumor M2-like phenotype and have substantial influences on tumor initiation and progression.
On the one hand, TAM-derived soluble molecules directly suppress the functions of tumor-infiltrating T cells and NK cells. Besides, autocrine IL and TNF-α stimulate PD-L1 upregulation on TAMs.
Also, TAMs directly suppress the antitumor immune response by recruiting Tregs and supporting their differentiation. On the other hand, TAMs also promote tumor progression in immune-independent ways, including tumor initiation and growth, angiogenesis, stemness, EMT, and distant metastasis.
b TAM-targeted therapies. TAMs could be harnessed by targeting their recruitment, activation, immune checkpoint pathways, and metabolism. Besides, macrophage-based cell therapies, such as nanoparticle-loaded monocytes, CAR-M, and genetically engineered hematopoietic progenitors, also show potent antitumor activities.
Abbreviations: TAM, tumor-associated macrophage; EMT, epithelial-mesenchymal transition; CSF1, colony-stimulating factor 1; CSF1R, CSF1 receptor; TLR, Toll-like receptor; STING, Stimulator of interferon genes; LILRB, Leukocyte immunoglobulin-like receptor B; SIRPα, Signal regulatory protein-α; IDO, Indoleamine 2,3-dioxygenase; CAR, Chimeric antigen receptor.
In parallel with the immunosuppressive effects, TAMs also promote tumor progression in immune-independent ways, including angiogenesis, stemness, treatment resistance, and distant metastasis [ ].
In gastric and colon cancers, chronic inflammation and oncogenic signals enhance the activities of multiple inflammation-associated transcription factors such as NF-κB, STAT3, and HIF-1α, recruiting macrophages into the TME [ ]. Subsequently, these recruited macrophages generate a panel of molecules e.
Also, TAMs induce epithelial-mesenchymal transition EMT of cancer cells by secreting CCL2, CCL5, CCL18, COX-2, MMP9, EGF, TGF-β, and IL-6 [ , , , , , , , ]. These paracrine cytokines from TAMs endow cancers with greater invasive and metastatic capacities [ ].
Furthermore, TAM-derived soluble molecules and TAM-tumor interactions maintain the stemness of cancer cells [ , , , ]. Moreover, TAMs support tumor growth by producing proangiogenic factors, including VEGFA, EGF, and TGF-β1 [ , , ]. Given the pivotal roles of TAMs in cancer development, intensive attempts have been made to delete TAMs or reprogram TAM behaviors.
Numerous studies have confirmed the protumor roles of TAM in the majority of human tumors. As a result, targeting TAMs has emerged as a promising therapeutic strategy for cancer patients Table 4. In the ensuing paragraphs, we summarize several TAM-based therapeutic strategies, including targeting TAM recruitment, activation, and metabolism Fig.
Besides, myeloid checkpoint inhibitors and macrophage cell therapies are promising, especially with present immune checkpoint blockade.
As mentioned above, TAM recruitment is driven by chemokines and CSF1. Although therapeutic antibodies or inhibitors targeting attractants such as CCL2-CCR2 e. Relatively, clinical trials of CSF1-CSF1R inhibitors e.
CSF1-CSF1R blockade deletes the TAM population, retards tumor growth, and increases treatment sensitivity [ , , ]. Besides, the CSF1R inhibitor BLZ could reprogram TAM from a tumor-promoting toward a tumor-suppressing phenotype, enhancing antigen presentation and T or NK cell activation [ ].
At present, more clinical studies of CSF1R inhibitors combined with other therapies are still ongoing. Some novel TAM depletion strategies, such as CAR-T cells recognizing folate receptor-β, eliminate M2-like TAM subsets and promote tumor-specific T-cell response [ ].
Furthermore, Lurbinectedin, which is a synthetic alkaloid, remodels the TME by prompting apoptosis in TAMs and diminishing the expression of CCL2.
Lurbinectedin has received approval for the treatment of small-cell lung cancer [ ]. Also, there have been recent advancements in the use of M2 macrophage-targeting peptides M2peps to specifically target and deliver pro-apoptotic agents to M2-like TAMs in preclinical tumor models [ ]. These therapeutic agents associated with M2peps demonstrate preferential toxicity towards M2-like TAMs and exhibit potent anti-tumor effects, holding promise for potential clinical applications in TAM-focused immunomodulation [ ].
Classical activation endows macrophages with antitumor properties. Agents enhancing classical activation pathways, including CD40, STING, and TLR, reset TAMs in the antitumor M1-like phenotype. As described above, CD40L-CD40 is the core pathway to activate antigen-presentation cells [ ].
Preclinical studies demonstrate that agonistic CD40 antibodies effectively arm macrophages with cytostatic activity against tumor cells, stimulating antitumor response and slowing tumor growth [ , ].
Furthermore, agonistic CD40 antibodies improve the antigen presentation capability of TAMs by upregulating costimulatory molecules and MHC expression [ ]. Besides CD40, agents targeting TLR exert immunostimulatory effects by enhancing the cytotoxic activity and chemokine production of TAMs [ , ].
Additionally, STING agonists promote IFN-I secretion and macrophage polarization toward the M1-like phenotype. The phagocytosis and cross-presentation capabilities of TAMs are constrained by immune checkpoints such as signal regulatory protein-α SIRPα , SLAM family receptors SFRs , sialic acid-binding immunoglobulin-like lectin Siglec , and leukocyte immunoglobulin-like receptor B LILRB families [ , , ].
Agents blocking the CDSIRPα axis improve macrophage phagocytosis, enhance programmed cell death of cancer cells, and promote macrophage-mediated ADCP or ADCC effects [ , , , , , ]. Besides, more anti-CD47 antibody-involved strategies achieve encouraging results in solid and hematological malignancies [ , , ].
Besides the CDSIRPα axis, other immune checkpoints, such as Siglec receptors, are also vital targets for cancer immunotherapy [ ]. Similar to PD-1 signaling, sialoglycan ligands bind to inhibitory Siglec receptors e.
Innate immune cells, especially TAMs, highly express Siglec receptors [ ]. In various cancers, tumor-derived ligands e. Actually, Siglec signaling undermines the functions of multiple immune cells, including but not limited to DCs, NK cells, and T cells.
Degenerating sialic acid residues by sialidase improves lymphocyte phagocytosis [ ]. Preclinical studies have demonstrated that Siglec blockade boosts antitumor immunity and inhibits tumor growth [ , ].
Interrupting CDSiglec interaction by anti-CD24 antibody improves phagocytic clearance of cancer cells by macrophages [ ]. Moreover, other immune checkpoints and scavenger receptors are also identified as important regulators for TAM polarization and functions, such as LILRB, PD-1, and P-selectin glycoprotein ligand 1 PSGL1 [ , , , , , ].
Driven by nutrient deprivation and hypoxia, dysregulated metabolic conditions in the TME promote the accumulation of TAMs [ ]. The by-product of glycolysis is lactic acid, which could promote the polarization of macrophages toward the M2-like phenotype [ ].
Agents targeting glycolysis, such as 2-deoxy-D-glucose 2-DG , reverse M2 polarization [ ]. Inhibiting tumor-derived retinoic acid induces the differentiation of monocytes toward immunostimulatory DCs rather than TAMs [ ].
Also, glutamine metabolism inhibitors retard tumor growth by rewiring TAMs toward the M1-like phenotype [ ]. Furthermore, IDO1-mediated tryptophan metabolism, tumor-derived PGE2, and oxysterol receptor LXR transcription factor also maintain the immunoinhibitory functions of TAMs [ , , ].
Agents blocking these molecules have immense potential and broad prospects. Apart from regulating tumor metabolites, other novel agents, such as anti-IL-1 antibodies and nanoparticles containing mRNAs encoding IRF5-IKKβ or miRNA, effectively reprogram TAMs toward antitumor effectors [ , , ].
The TAM pool is dynamically replenished by peripheral circulating monocytes, which are constantly trafficked into the TME. Therefore, monocytes could be used as Trojan horses to delivery agents into tumors [ , , ].
Nanoparticle-loaded monocytes exhibit superior antitumor activity to free nanoparticles [ ]. Also, genetically engineered hematopoietic progenitors with high expression of Tie-2 and IFN-α effectively migrate to tumors and reshape the TME by releasing IFN-α [ ].
Genetically engineered myeloid cells highly expressing IL improve T cell response and inhibit tumor growth [ ]. Furthermore, engineered particles containing cytokines such as IFN-α adhering to macrophage surfaces could facilitate TAMs to maintain their antitumor phenotype in the hostile TME [ ].
Apart from engineering macrophages for drug delivery, macrophage engineered with CAR CAR-M therapy is also a promising manner to mobilize antitumor immune response [ , ]. Similar to CAR-T cells, CAR-M contains extracellular antigen-recognizing, transmembrane, and intracellular domains. However, ZAP, a kinase for T cell activation, is not available in macrophages.
Instead, CAR-M transduces phagocytic signals by another kinase Syk, which contains tSH2 domain and binds to CD3ζ [ ]. Besides CD3ζ, other domains with immunoreceptor tyrosine-based activation motifs ITAMs , such as multiple epidermal growth factor-like domains protein 10 Megf10 and Fc receptor FcRγ , also elicit phagocytosis of macrophages [ , ].
CD3, CD, FcR, and Megf10 are commonly utilized intracellular signaling domains in CAR-M products [ ]. The first CAR-M product was developed in , initially referred to as CAR-phagocytes CAR-Ps , by employing a lentiviral vector to introduce a CAR with either Megf10 or FcRγ as the cytosolic domain into mouse macrophages [ ].
These CAR-Ps displayed specific engulfment of entire human cancer cells, particularly when a tandem PI3K p85 subunit was integrated into the CAR.
Although this study primarily focused on the impact of CAR on phagocytosis while excluding other essential anti-tumor functions carried out by macrophages, it marked a significant milestone in CAR-based immunotherapy [ ].
Moreover, CAR-M cells possess the capacity to stimulate the transformation of M2 macrophages into M1 and release proinflammatory cytokines in the TME. It was reported that anti-HER2 CAR-M cells not only displayed tumor-killing capabilities but also induced a proinflammatory TME.
Additionally, CAR-M products could enhance the activity of tumor-specific T cells by generating proinflammatory chemokines and cytokines, reprogramming M2-like into M1-like macrophages, and increasing the expression of antigen presentation machinery [ ].
Furthermore, the extracellular matrix ECM hampers immune cell infiltration into the TME, limiting the efficacy of immunotherapy. In contrast, macrophages are naturally attracted to the TME, break down the ECM, and consequently represent the most abundant immune cell population in tumors by secreting MMPs.
Shen et al. engineered CAR-M cells utilizing CD as the intracellular signaling domain referred to as CAR M. They observed that when these CAR M cells were co-cultured with target cells, there was a significant increase in MMP expression. Although this boost in MMPs did not affect tumor cell proliferation in vitro, CAR M cells rapidly accumulated at the tumor site when administered in vivo.
This led to a reduction in tumor collagen deposition and promoted the infiltration of immune cells, ultimately resulting in significant tumor suppression [ ].
Generally, CAR-M has some advantages over CAR-T cells in solid tumors, especially enhanced trafficking and infiltration into the TME [ , ]. At present, most CAR-M products are at the preclinical stage, and only one autologous CAR-M targeting Her-2 is in clinical evaluation CT, NCT, Phase 1 [ , ].
In addition to Trojan horse strategies and CAR-M, there exist combinations that merge elements from both strategies. Nanocomplexes comprised of nanocarriers designed for macrophage targeting and plasmid DNA encoding CAR-interferon-γ, when administered in vivo, induce the development of CAR-M1 macrophages.
These specialized macrophages exhibit the ability to engage in CAR-mediated cancer cell phagocytosis, orchestrate anti-tumor immunomodulatory responses, and effectively impede the growth of solid tumors [ ]. MDSCs are a heterogeneous population of cells with immunosuppressive effects [ ].
Under normal physiological conditions, bone marrow cells differentiate into mature subsets, including DCs, macrophages, and granulocytes also termed terminally differentiated cells [ ]. However, the differentiation process of MDSC is disturbed by the TME, arresting it in an immature state [ ].
The immunosuppressive nature of MDSCs contributes to cancer progression by promoting immune evasion and treatment resistance.
For several solid tumors and hematologic malignancies, elevated levels of MDSCs have been associated with poor prognosis and treatment response [ , , , , , , , , ]. Understanding the role of MDSCs in cancer is crucial for developing effective therapeutic strategies.
Targeting MDSCs and modulating their immunosuppressive functions may hold promise in enhancing antitumor immune responses and improving patient outcomes. MDSCs could be mainly classified into two cell subsets named polymorphonuclear MDSC PMN-MDSC, similar to neutrophils in phenotype and morphology and monocytic MDSC M-MDSC, similar to monocytes in phenotype and morphology [ ].
In mice, MDSCs are distributed in peripheral blood, bone marrow, spleen, lung, liver, and tumors. In humans, MDSCs are distributed in peripheral blood and tumors. The primary characteristic of MDSCs is immune suppression. Although MDSCs have been implicated in undermining the functions of multiple immune cells, their main targets are T cells.
MDSCs cause immune suppression by upregulating TGF-β, IL, IDO, iNOS, ARG1, PEG2, reactive oxygen species ROS , PD-L1, and depleting cystine and cysteine in the TME Fig. Besides, the ADAM17 on MDSCs exerts immunosuppressive effects by downregulating L-selectin T cell homing receptor on naïve T cells [ , ].
It has been confirmed that PMN-MDSCs and M-MDSCs prefer different manners to inhibit T cell response. PMN-MDSCs preferentially produce ARG1, ROS, peroxynitrite, and PGE2, while M-MDSCs preferentially generate NO, TGF-β, and IL [ , , ]. Apart from cytotoxic T cells, MDSCs impair other tumoricidal immune cells, including DCs, B cells, and NK cells [ , , ].
Furthermore, MDSCs weaken antitumor immunity by inducing the differentiation or enhancing the functions of immunosuppressive cells such as TAMs and Tregs [ , , ]. MDSC-mediated T cell suppression and MDSC-targeted therapies. a MDSC-mediated T cell suppression. MDSCs cause immune suppression by upregulating TGF-β, IL, IDO, iNOS, ARG1, ROS, PD-L1, and depleting cystine and cysteine in the TME.
Besides, the ADAM17 on MDSCs exerts immunosuppressive effects by downregulating L-selectin T cell homing receptor on naïve T cells. b MDSC-targeted therapies can be categorized into four groups: suppressing the recruitment and expansion of MDSCs; facilitating the differentiation of MDSCs into mature myeloid cells; counteracting the functions of MDSCs; and directly depleting MDSCs.
In addition to exerting immunosuppressive effects, MDSCs contribute to tumor progression by promoting tumor angiogenesis, maintaining cancer stemness, inducing EMT, and facilitating premetastatic niche formation [ ].
On the one hand, MDSCs support vascularization by generating VEGF and MMP-9 [ ]. On the other hand, some MDSCs have the potential to differentiate toward endothelial-like cells, directly incorporating into tumor endothelium [ ].
Moreover, exosomal SA9 released by MDSCs increases the stemness of colorectal cancer in a HIF-1α-dependent manner [ ]. MDSC-endowed stemness qualities are also observed by triggering STAT3-NOTCH crosstalk and inducing miRNA in breast and ovarian cancer cells [ , ]. The significant involvement of MDSCs in tumor development has sparked the exploration of MDSC-targeted therapies.
These strategies can be categorized into four groups: 1 suppressing the recruitment and expansion of MDSCs; 2 facilitating the differentiation of MDSCs into mature myeloid cells; 3 counteracting the functions of MDSCs; and 4 directly depleting MDSCs Table 5 Fig.
Besides, IL-1β contributes to the recruitment and expansion of MDSCs and modulates their immunoinhibitory functions in the TME [ ].
Inhibiting IL-1β or NLRP3 inflammasome a key component for IL-1β maturation reduces MDSCs and enhances antitumor immunity in head and neck squamous cell carcinoma models [ , , , , ].
Additionally, GM-CSF leads to MDSC accumulation and weakens cancer antigen-specific T-cell response [ ]. At the same time, G-CSF initiates MDSC mobilization and promotes tumor angiogenesis [ ].
Furthermore, anti-VEGF-VEGFR therapies also inhibit MDSC recruitment by blocking VEGFR1 signaling of MDSCs [ , ]. All-trans retinoic acid ATRA regulates cell differentiation, proliferation, and apoptosis by nuclear retinoid receptors [ ]. Differentiation therapy with ATRA has altered the therapeutic paradigm of acute promyelocytic leukemia and significantly improved patient outcomes [ ].
Similarly, ATRA could promote the differentiation of immature MDSCs toward terminated differentiated myeloid cells DCs, macrophages, and granulocytes [ ].
In multiple clinical trials of lung cancer NCT and melanoma NCT , additional ATRA treatment significantly augments immunotherapy and chemotherapy [ , , ]. Moreover, constitutive STAT3 activation prevents the differentiation of immature myeloid cells and maintains their immunosuppressive properties [ , ].
In patients with diffuse large B-cell lymphomas, AZD antisense oligonucleotide of STAT3 reduces peripheral PMN-MDSCs as well [ ].
The synergistic effects between STAT3 inhibitors and immunotherapies have been validated in a series of preclinical and clinical studies [ , , , , ]. TLRs also play an important role in the maturation and differentiation of MDSCs.
In vivo experiments demonstrate that CpG effectively promotes the maturation of MDSC and abrogates MDSC-mediated T-cell suppression by triggering IFN-α production of pDCs [ ].
Furthermore, some novel agents, such as curcumin, β-glucans, and icariin, drive the differentiation of MDSCs into DCs and macrophages and undermine their suppressive functions [ , , ].
The COXPGE2 axis is the key pathway to maintain the immunosuppressive functions of MDSCs [ , , ]. On the one hand, PGE2 in the TME attracts MDSCs by CXCLCXCR4 [ ]. Besides, paracrine PGE2 induces MDSCs to upregulate COX-2 expression, which could stimulate autocrine PGE2 production, forming a positive feedback loop [ ].
This PGE2-COX-2 positive feedback loop facilitates to stabilize MDSC phenotype [ ]. Agents targeting COXPGE2 signaling hamper the immunoinhibitory functions of MDSCs and improve the sensitivity to immunotherapies [ , ].
For example, celecoxib COX-2 inhibitor decreases the production of ROS and NO in MDSCs and reverses T-cell tolerance [ ]. Besides, celecoxib combined with CD40 agonist therapy effectively increases CXCL10 but reduces ARG1 in MDSCs. As a result, antitumor immunity is restored, and tumor growth is suppressed in glioma-bearing mice [ ].
Additionally, phosphodiesterase 5 PDE5 inhibitors such as tadalafil and sildenafil reduce the levels of ARG1, iNOS, and IL-4Rα myeloid suppressor cell suppressive marker [ , ]. In clinical studies of melanoma EudraCT: — and head and neck squamous cell carcinoma NCT and NCT , tadalafil reduces MDSC frequency, hampers the immunoinhibitory properties of MDSCs, and augments cancer-specific immunity [ , , ].
Moreover, epigenetic regulators such as histone deacetylase inhibitors HDACis have substantial influences on the functions of MDSCs. In murine tumor models, HDACi treatment significantly downregulates the expression of COX-2, ARG1, and iNOS in MDSCs [ , ].
The class I HDACi entinostat mainly modulates the functions of PMN-MDSCs, while class II HDAC6 inhibitor ricolinostat primarily regulates the functions of M-MDSCs [ ].
Moreover, other novel agents such as Nrf2 activator CDDO-Me , vitamin D3, and nitroaspirin the derivative of aspirin with nitro moiety are identified as negative regulators for MDSC-mediated immunosuppression [ , , ]. The functions of MDSCs could be suppressed by disturbing their metabolism.
Due to the high consumption and active fatty acid oxidation FAO of MDSC, inhibiting some key molecules in FAO impedes MDSC-mediated immune suppression [ ]. Agents targeting FAO rate-limiting enzymes such as etomoxir targeting enzyme CPT1 and lipofermata targeting enzyme FATP2 remarkably abrogate the immunosuppressive activities of MDSCs in the TME [ , ].
In addition to fatty acid metabolism, glycolysis also has positive effects on the survival and activity of MDSCs.
In murine tumor models, tumor-infiltrating MDSCs have more active glycolysis and mTOR signaling [ ]. Rapamycin mTOR inhibitor downregulates the quantity and activity of M-MDSCs in mice [ ]. It is important to note that certain agents affecting metabolism can also impact immune cells within the TME apart from MDSCs.
Additionally, the peroxisome proliferator-activated receptor agonist Bezafibrate stimulates mitochondria, enhancing oxidative phosphorylation, glycolysis, and FAO, ultimately leading to improved functionality in T cells infiltrating tumors [ ].
Furthermore, the costimulatory signal BB enhances the glucose and fatty acid metabolism in T cells to meet their growing energy demands. The effects on the T cell cycle and anti-apoptotic activity mediated by BB signaling are entirely nullified by the FAO inhibitor etomoxir [ ]. Furthermore, the impact of immunometabolism on other immune cells, such as DCs and macrophages, has been confirmed.
The anabolic and catabolic processes substantially influence the immunogenicity and tolerogenicity of DCs, while succinate and citrate directly regulate macrophage functions [ ].
Hence, it is essential to comprehensively consider the effects of metabolism-modulating agents on various components of the TME beyond MDSCs to achieve optimal immunotherapy efficacy.
Some chemotherapeutic agents could selectively eradicate regulatory immune cells, especially MDSC, and alleviate immune suppression [ ]. Carboplatin and paclitaxel cause MDSC depletion and boost therapeutic vaccination-mediated immune response [ ].
Besides, low-dose capecitabine reduces circulating MDSCs and increases cytotoxic immune infiltration in the TME [ ]. It is notable that some cytotoxic agents might also have positive effects on MDSCs, such as cyclophosphamide CTX.
The difference could be attributed to agents, administration schedules and doses, and heterogeneity of sampling [ ]. Generally, these agents are not MDSC-specific, with cytotoxic effects on all rapidly proliferating, even lymphocytes in the TME.
Relatively, therapies targeting CD33 have better specificity for MDSCs [ ]. Fc-engineered anti-CD33 antibodies BI and anti-CD33 antibody-conjugated drug gemtuzumab ozogamicin could specifically eliminate MDSCs [ , ].
Additionally, agonists of TNF-related apoptosis-induced ligand TRAIL receptors and anti-angiogenesis tyrosine kinase inhibitor sunitinib are regarded as MDSC eliminators as well [ , ]. Collectively, MDSCs play a crucial role in tumor development, leading to the exploration of four main categories of MDSC-targeted therapies.
These approaches include 1 suppressing MDSC recruitment and expansion through blockade of chemokine pathways and cytokines, 2 promoting MDSC differentiation into mature myeloid cells using agents like ATRA, STAT3 inhibitors, and TLR agonists, 3 countering MDSC functions by targeting the COXPGE2 axis and metabolic pathways, and 4 directly depleting MDSCs, often through chemotherapeutic agents like 5-fluorouracil and gemcitabine or specific MDSC-targeting therapies like anti-CD33 antibodies.
Notably, some metabolic modulators can affect other immune cells in the TME. These strategies offer potential in enhancing cancer immunotherapy by either reducing MDSC numbers or neutralizing their suppressive functions, but their broader effects on immune cells need to be considered for optimal outcomes.
NK cells are a type of immune cell that make up the innate lymphoid cellular defense and surveillance system [ , ]. When encountering tumor cells, it serves as the primary sentinel in safeguarding organismal health. In humans, NK cells lack membranal TCR and CD3 molecules but have neural cell adhesion molecule NCAM, also known as CD56 , along with activating and inhibitory receptors [ , ].
Particularly, unlike other surface biomarkers only found in the bloodstream, CD is an activating receptor that can also identify NK cells in formalin-fixed paraffin-embedded tissue specimens [ ].
NK cells can be activated and exert cytotoxic effects independent of specific antigen recognition, as they recognize foreign organisms and malignancies through the aforementioned stimulatory and inhibitory receptors [ ]. It is well established that human NK cells proceed through five discrete stages in lineage derivation and development [ ].
A subset of these progenitors is committed into α-lymphoid precursor αLP cells by expressing integrin α4β7 [ , ]. Subsequently, αLP cells expressing CXCR6 are able to develop into precursor NK and ILC-3 subtypes [ ]. The symbolic event of precursor NK occurrence is the IL-1R1 expression on αLP cells [ , ].
Predominant precursor NK cells undergo further development and maturation in bone marrow, while a minority of cells undergo maturation in peripheral lymphoid organs [ , ].
In these sites, NK cells gradually express specific surface receptors driven by multiple transcription factors, including T-bet, Id2, E4BP4, and Eomesodermin Eomes [ , , , ].
In brief, NK cell development involves dynamic changes in lineage-specific biomarkers, with a gradual decrease in progenitor and precursor markers and an increase in bioactive receptors. The trafficking, homing, and activation of NK cells are mutually reinforcing processes that complement the maturation of these cells.
Specifically, immature NK cells require certain factors to facilitate their trafficking during maturation. Most NK cells undergo maturation within a specialized niche located in bone marrow, where they are surrounded and nourished by parenchymal sinusoidal vessels [ ].
Only after CXCR4 is downregulated, NK cells migrate from bone marrow into the sinusoidal vessel and subsequently into peripheral blood [ ]. Additionally, various chemokines and integrins, along with their corresponding receptors and ligands, are involved in this process.
Therefore, distinct types of chemokines and integrins can be identified as biomarkers for circulating or tissue-resident NK cells [ , ]. The migration of NK cells from sinusoidal vessels into circulation also needs the participation of various factors, particularly CX3CR1, S1P5, and CXCR6 [ , , , , , ].
Additionally, CX3CR1 boosts the infiltration of NK cells into the central nervous system, which is traditionally considered the forbidden zone for immune cells [ , ]. In these sites, they exert more secretory biologic function rather than cell lysed function [ , , ].
After licensing, NK cells are directly activated, equipped with a diverse array of inhibitory and activating surface receptors, independent of MHC-restricted antigen recognition when encountering detrimental factors [ ].
In the TME, NK cells are activated by the construction changes or expression downregulation of MHC-I molecules [ ]. Also, NK cells can be activated by stimulatory receptors such as NKp30, NKp44, and NKp46 [ ]. Additionally, the CD16 receptor on NK cells exerts separate activating functions after being engaged by the immunoglobulin-opsonized cells.
This process elicits the phosphorylation of the ITAM domain of FcεRIγ and CD3ζ on the surface of NK cells, ultimately culminating in ADCC [ , ]. However, the antitumor activity of NK cells is limited by multiple factors, such as insufficient NK cell infiltration and the hostile TME [ , ].
It has been validated that cancer-derived exosomes and hypoxia could blunt NK cell activity [ , ]. Besides, some modulatory immune cells and cytokines, such as TGF-β, activin-A, and adenosine, also contribute to the immunosuppression of tumor-infiltrating NK cells [ , , , , ].
High NK cell abundance in the TME predicts a favorable prognosis in a myriad of cancers [ , , , ], and NK cells suppress tumorigenesis by executing immunosurveillance [ , ].
In the TME, NK cell activation is determined by activating and inhibiting signals, such as NKG2D, 2B4, DNAM1, LFA1, CD28H, IL, IFN-α and TGF-β Fig. Notably, HLA-E exerts dualistic immunoregulatory effects on NK cells when binding to different receptors [ , , , , ]. Activated NK cells can eliminate tumor cells by releasing perforin and granzymes, as well as by inducing apoptosis via ADCC, FasL, or TRAIL [ , ].
Besides, NK cells secrete cytokines, including IFN-γ and TNF-α, which lead to tumor growth arrest [ ]. The ruptured tumor cells will unleash neoantigens, subsequently prompting the adaptive immune response [ ]. As the communicative bridge between innate and adaptive immunity, DC plays crucial and intricate roles in antitumor immune responses.
Additionally, NK cells promote the recruitment of cDCs into the TME [ 57 ]. A novel type of NK cells, termed induced pluripotent stem cells iPSCs -derived NK cells, is reported to recruit T cells into the TME and augment the therapeutic effect of immune checkpoint inhibitors [ ].
The mechanisms underlying the recognition of tumor cells by NK cells highlight the perspectives for NK cell-targeted strategies, particularly in cold tumors lacking neoantigens. Interaction between NK cell and the TME.
Schematic diagram depicting primary receptors expressed by NK cells and their corresponding ligands on tumor cells or cytokines in the TME. Activating stimulative receptors triggers an intracellular signaling cascade that activates NK cells and vice versa.
The two factors dynamically modulate the behavioral pattern of NK cells, whose disequilibrium may lead to immune evasion or clearance. Abbreviations: NK cell, natural killer cell; TME, tumor microenvironment; Ecto-CRT, ecto-calreticulin; A2AR, A2a adenosine receptor; ACVR1, activin receptor type 1.
The antitumor activity of NK cells has been unequivocally demonstrated through in vitro experiments and animal models, providing a solid rationale for investigating their potential as anticancer agents [ , , ].
Generally, NK cell-based therapeutic strategies can be categorized into five distinct groups based on the sequential processes of NK cells, including trafficking, activation, effector function execution, and secondary adaptive immune priming, which synergistically reinforce each other Fig.
NK cell-based therapeutic strategies. a NK cell-based therapeutic strategies could enhance multiple biological processes, including trafficking, activation, tumor-killing activity, and NK cell-mediated secondary adaptive immune priming.
b NK cell-based therapeutic strategies. The green box denotes the biological process targeted by the corresponding strategy, while the red box denotes the biological process not involved in the corresponding strategy. Researchers are testing vaccines for many types of cancer, including:. Bladder cancer.
Researchers are testing how well a vaccine made from a virus altered with the HER2 antigen works. These antigens or molecules live on the surface of some bladder cancer tumors. The virus may help teach the immune system to find and destroy these tumor cells.
Researchers also want to know which works better: standard bladder cancer treatment or standard treatment with a vaccine. Brain tumors. There are many studies testing treatment vaccines aimed at certain molecules on the surface of brain tumor cells.
Some focus on newly found brain cancer. Others focus on cancer that has come back, or recurred. Many of the studies include children and teens. Breast cancer. Many studies are testing treatment vaccines for breast cancer, given alone or with other treatments. Other researchers are working to get vaccines that prevent breast cancer into clinical trials.
Cervical cancer. As explained above, the FDA approved HPV vaccines that prevent cervical cancer. Research continues on vaccines that help treat each stage of cervical cancer. Colorectal cancer. Researchers are making treatment vaccines that tell the body to attack cells with antigens thought to cause colorectal cancer.
These antigens include carcinoembryonic antigen CEA , MUC1, guanylyl cyclase C, and NY-ESO Kidney cancer. Researchers are testing many cancer vaccines to treat kidney cancer. They are also testing vaccines to prevent kidney cancer in its later stages from coming back.
Studies are looking at treatment vaccines for various types of leukemia, such as acute myeloid leukemia AML and chronic lymphocytic leukemia CLL. Other vaccines made from a person's cancer cells and other cells may help the immune system destroy the cancer.
Researchers are testing many melanoma vaccines, given alone or with other treatments. Destroyed melanoma cells and antigens in the vaccines tell the immune system to destroy other melanoma cells in the body. There are many clinical trials looking at vaccines for people with multiple myeloma who are near remission.
This means doctors can no longer find the cancer in the body and there are no symptoms. Pancreatic cancer. Researchers are working on many treatment vaccines designed to boost the immune system's response to pancreatic cancer cells.
The vaccine may be given as the only treatment or along with another treatment. Prostate cancer. As noted above, sipuleucel-T is a vaccine that doctors can use to treat people with prostate cancer that has spread.
Now studies are looking to see if the vaccine can help people with prostate cancer at earlier stages. Learn more about the latest research for specific cancers in this website's guides and finding a clinical trial. If you want to learn more about joining a cancer treatment vaccine clinical trial, talk with your health care team.
You may want to ask these questions:. How is the vaccine made? Will I need blood cells or tumor tissue removed to make the vaccine?
How will you remove it? Making Decisions About Cancer Treatment Clinical Trials. National Cancer Institute: Cancer Treatment Vaccines. Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology ASCO , the voice of the world's oncology professionals.
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Request Permissions. Approved by the Cancer. Are there vaccines that prevent cancer? Food and Drug Administration FDA : HPV vaccine. The FDA has approved HPV vaccines to prevent: Cervical , vaginal , and vulvar cancers Anal cancer Genital warts HPV can also cause other cancers the FDA has not approved the vaccine for, such as oral cancer.
Are there vaccines that treat cancer? They can: Keep the cancer from coming back Destroy any cancer cells still in the body after treatments end Stop a tumor from growing or spreading How do cancer treatment vaccines work?
Sipuleucel-T is tailored to each person through a series of steps: White blood cells are removed from the person's blood. The white blood cells are altered in a laboratory to target prostate cancer cells.
What are the challenges of using treatment vaccines? Making treatment vaccines that work is a challenge because: Cancer cells suppress the immune system. Vaccines and clinical trials Clinical trials are key to learning more about both cancer prevention vaccines and cancer treatment vaccines.
Researchers are testing vaccines for many types of cancer, including: Bladder cancer. Lung cancer. Lung cancer treatment vaccines in clinical trials target antigens. Questions to ask your health care team If you want to learn more about joining a cancer treatment vaccine clinical trial, talk with your health care team.
You may want to ask these questions: Is there a clinical trial testing a vaccine for my type and stage of cancer? Where is the clinical trial located? What is the vaccine and how does it work? How will I receive the vaccine and how often? How long will I need the vaccine?
Although Aging and wellness has great potential, it is currently only immuhity to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with cacner oxidative stress and sports injuries load and microsatellite Enhancrd, and Enhanced immunity against cancer in these types of tumors, immunotherapy is not effective for all patients. In order cander belly fat burning the effectiveness of tumor immunotherapy, Regular check-ups article reviews the research progress of tumor canccer immunotherapy, Enhance studies the oxidative stress and sports injuries of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment TME and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. The agains system is agsinst system Enhznced your Enhanced immunity against cancer that fights off infection. Immunotherapy is Weight gain goals form of medical treatment oxidative stress and sports injuries activates your immune system to help fight cancer. There are many different types of immune cells in your body. Different cells fight different types of cancer. This protects healthy cells. This can make the immune system stop the attack on the cancer too early. This lets the T cells keep fighting cancer.
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