The mechanism of cytokine regulation of cancer occurrence and development in the tumor microenvironment and its application in cancer treatment: a narrative review

Introduction

Background

The tumor microenvironment (TME) is a dynamic and complex cellular milieu comprising leukocytes, fibroblasts, extracellular matrix (ECM), and tumor cells. Beyond providing structural support for tumor tissues, the cellular constituents of the TME release a plethora of chemokines, cytokines, and members of the tumor necrosis factor superfamily (TNFSF), all of which facilitate tumor cells proliferation and emigration (1). Moreover, the TME is vitally important for delaying the response of tumor cells to chemotherapy and interfering with immune surveillance, both contributing to tumor growth (2).

The ratio and composition of different cytokines and chemokines within the TME significantly influence the complex intercellular interactions, including promoting cell invasion and migration, evading immune destruction, inducing tumorigenesis, resisting apoptosis, and maintaining cell proliferation signaling (3). Recognizing the pivotal role of the TME in these processes presents an opportunity to target specific components or signaling pathways within the TME for therapeutic intervention. In the process of tumor initiation and development and treatment resistance, cytokines targeting TME have been paid more and more attention in immunotherapy trials.

Rationale and knowledge gap

Despite the potential benefits of cytokine-based therapies, several obstacles must be addressed before their widespread therapeutic application. The safe utilization of cytokines is hindered by their frequent severe toxicities, such as cytokine storm and vascular leakage syndrome. Furthermore, the interconnections and mechanisms of action of cytokines remain poorly understood. Complicating matters, cytokines exhibit a spectrum of effects, including both pro-tumor and anti-tumor actions, adding layers of complexity to their therapeutic potential (4). To overcome these challenges, scientists have developed cutting-edge therapies, including recombinant interleukins (ILs) and antibody-cytokine fusion proteins, laying the groundwork for further advancements. For instance, in a mouse glioma model, the antibody-cytokine fusion protein L19TNF has demonstrated viability. When combined with CCNU, L19TNF enhances immune cell infiltration into the tumor, triggers immune-stimulatory pathways, and suppresses immune-suppressive pathways, resulting in significant tumor regression (5). Another engineered cytokine, F10 IC-CBD, conjugates human IL-2 to anti-IL-2 antibodies. F10 IC-CBD reduces the required dosage and administration frequency by prolonging the half-life of IL-2 and improving its pharmacokinetic and pharmacodynamic properties (6).

Objective

This paper aims to review recent advancements in novel immunotherapy strategies arising from the interactions between TME and tumor cells. Additionally, we aim to synthesize the latest research progress concerning the role of major cytokines in regulating tumor development within the tumor immune microenvironment. Through the presentation of specific examples of tumor immunotherapy, we endeavor to deepen readers’ understanding of the application of cytokines in the TME. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-679/rc).

Methods

A thorough literature search was carried out on the PubMed and Web of Science databases to identify pertinent studies elucidating the mechanisms of cytokine utilization in tumor immunotherapy and the regulation of tumor occurrence and development. Key search terms included “tumor immunotherapy”, “cytokines”, “chemokines”, “tumor microenvironment”, “recombinant cytokine engineering”, and “tumor necrosis factor superfamily”. Only English-language literature was considered, and the search strategy is detailed in Table 1.

TME

The TME is widely acknowledged as a sanctuary for tumor cells, having a significant effect on the development, metastasis, and carcinogenesis by continually providing essential nutrients and other vital components necessary for tumor cell survival. Previous studies have illustrated that the TME is a dynamic network comprising various elements, including tumor cells, the ECM, endothelial cells, and fibroblasts. The interplay among these components creates physiological and pathological characteristics in tumor cells, such as low pH, hypoxia, hyperthermia, and high pressure (7). The TME, encompassing ECM, immune cells and inflammatory cells, serves as the internal milieu for tumor development and persistence (8,9). Predominantly constituted by immune and non-immune cells (10). These cellular components include tumor cells, neurons, and endothelial cells. Immune cells in the TME comprise tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), dendritic cells (DCs), T cells, B cells, and natural killer (NK) cells, each exerting anti-tumor or pro-tumor effects based on their effector capabilities (11). Furthermore, hypoxia, acidic environments, endogenous hydrogen peroxide, and altered expression of ECM proteins denote crucial TME alterations pivotal for tumor metabolism and progression (12). These distinctive features facilitate the induction of immunological responses by an array of cytokines, including chemokines, TNFSF members, and interleukins, underscoring their potential as therapeutic targets in cancer treatment.

Interleukin

The role of ILs in tumor immunity

ILs play a crucial role in tumor initiation, metastasis, and progression. Among cytokines, specific ILs are intricately involved in the formation and advancement of tumors. Beyond their essential role in anti-tumor immune responses, ILs create an environment conducive to tumor formation (13). Increasingly, research indicates that ILs and their receptors can serve as therapeutic drugs and targets, offering anti-tumor efficacy, as outlined in Table 2.

The role of recombinant ILs in tumor immunotherapy

Despite their extensive history of use in treating cancers and other illnesses, cytokines exhibit several unfavorable pharmacological characteristics, including polypharmacy and broad systemic effects, which can limit their therapeutic efficacy and cause significant toxicity (30). Consequently, recombinant ILs are gaining popularity as a novel approach to tumor immunotherapy, aiming to elicit substantial anti-tumor responses. The application of recombinant ILs in tumor immunotherapy, particularly IL-2, IL-10, IL-15, IL-18 and IL-21, has garnered an increase in recent scientific developments. IL-mediated signaling pathways are involved in promoting a role in the development of tumor or antitumor processes, as shown in Figure 1.

Figure 1 The signaling pathways mediated by interleukins that are involved in anti-tumor responses or the promotion of tumor occurrence and development. JAK, Janus kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated protein kinases 1/2; PI3K/AKT, phosphatidylinositol 3-kinase/protein kinase B; TYK2, tyrosine kinase 2; TRAF6, tumor necrosis factor receptor-associated factor 6; MyD88, myeloid differentiation primary response 88; IRAK, receptor-associated kinase; NF-κB, nuclear factor kappa-B; IL, interleukin; SHC, Src homology and collagen.

Activated DCs and CD8⁺ T lymphocytes serve as the primary sources of IL-2 upon antigen stimulation (31). The first IL effectively utilized in cancer therapy is IL-2, which promotes the proliferation and differentiation of T cells and boosts the activation of NK and T cells, both of which inhibit the development and migration of malignant cells (32). Consequently, IL-2 can be employed as a tumor immunotherapy agent. However, high doses are associated with severe adverse effects that may be life-threatening. Bempegaldesleukin represents a pegylated IL-2 variant designed to mitigate such risks. Bempegaldesleukin has not yet received full approval and is still in the clinical trial stage. Conjugation with polyethylene glycol blocks IL-2’s binding site to the high-affinity component IL-2Rα, thereby extending its half-life and reducing the risk of overdose (33).

IL-10 exhibits promise as a prospective anti-tumor treatment, because of its anti-inflammatory properties and capacity to activate cytotoxic T lymphocytes (CTLs). However, IL-10 plays a complex part in regulating anti-tumor immunity, as it can exert inhibitory effects on other effector immunological cells like CD8⁺ T lymphocytes and NK cells while facilitating the survival, proliferation, and migration of tumor cells (34,35). As of now, Pegilodecakin is still in the clinical trial stage. Pegilodecakin, a pegylated IL-10 variant, induces systemic immune activation and CD8⁺ T cell-mediated immune responses in tumor patients by stimulating the production of IFN-γ and granzyme B. This suggests that pegylated IL-10 has the potential to enhance CD8⁺ T lymphocyte responses and reduce tumor growth, thus achieving a promising therapeutic effect (36).

IL-15 stimulates the proliferation and activation of tumor-infiltrating lymphocytes (TILs) while facilitating the transport of white blood cells, along with the activation and expansion of CTLs and NK cells. BJ-001 is the first IL-15 fusion protein targeting tumors, which is currently in the clinical trial stage. Beyond addressing the issue of its short half-life, BJ-001 also enhances therapeutic efficacy and reduces systemic toxicity through the incorporation of tumor-targeting molecules within its structural domains. These molecules facilitate enrichment in tumors expressing high levels of αvβ3, αvβ5, and αvβ6 integrins (37). In mouse tumor models, ALT-803, a super-agonist compound of IL-15 that enhances the activation and multiplication of NK cells, has demonstrated potent antitumor activity (38). At present, ALT-803 has progressed into multiple stages of clinical trials.

It was initially discovered that IL-18 stimulates Th1 cells to produce the cytokine IFN-γ, thereby inducing Th1 cell proliferation and activation. Additionally, IL-18 can upregulate TILs by activating various signaling pathways, thereby strengthening the immune system’s ability to combat tumors (39). Nevertheless, the therapeutic efficacy of targeted therapy is restricted, potentially due to the suppression of IL-18 signaling by IL-18 binding protein (IL-18BP), which exhibits a higher affinity for IL-18 than IL-18R. Currently, scientists have successfully developed the “decoy-resistant” IL-18 (DR-18), which is still in the clinical trial phase. It can stimulate the production of multifunctional CD8⁺ T cells and boost NK cells activity. Recent research highlights the robust production of IL-8 in the tumor tissues of chemotherapy-resistant patients, primarily secreted by cancer-associated fibroblasts (CAFs) (40,41). These findings offer a novel avenue for enhancing chemotherapy effectiveness and improving the prognosis of tumor patients, underscoring the vital function of IL-8 in mediating tumor cell resistance to chemical treatments.

IL-21 is mainly generated by T follicular helper cells (Tfh) and NK cells. Notably, IL-21 is essential for stimulating Th17 cells proliferation, facilitating Tfh cells formation, and enhancing the survival rates of CD8⁺ T cells, all of which may be conducive to its anti-tumor effects (42). This multifunctional cytokine also participates in inhibitory regulation, homeostatic maintenance, and lymphocyte differentiation. However, systemic administration fails to achieve sufficiently high concentrations within the TME to activate TILs due to IL-21’s short half-life and peripheral depletion (43). To circumvent this limitation, researchers have developed mutant proteins by conjugating IL-21 cytokines with antibodies. These protein conjugates have the potential to enhance the pharmacokinetic properties of IL-21, prolonging its half-life and reducing the frequency of dosing (44).

Chemokine

Chemokines constitute a group of structurally related, small, secreted cytokines that are essential for immune system regulation (45). These chemokines are categorized into subfamilies including CC, CXC, and CX3C, distinguished by the number and arrangement of their N-terminal cysteine residues, representing the largest subfamily of cytokines. Chemokines have intricate functions as pro- and anti-tumor agents in the setting of tumor immunity, owing to their diverse and dynamically regulated expression by immune cells, stromal cells, and tumor cells (46). Chemokine receptors, comprising a superfamily of seven transmembrane G-protein coupled receptors, are expressed not only on neutrophils and macrophages but also on endothelial and some epithelial cells derived from tumors (47). Chemokines are generated by immune and stromal cells infiltrating tumor tissues in TME, thereby modulating the tumor immune response. Additionally, tumor cells typically exhibit chemokine receptor expression, and the resulting chemokines may influence tumor cell growth, metastasis, and stemness (48). The progression of the disease has a major impact on patient prognosis and treatment, which is partly influenced by chemokines and particular receptors. These molecules participate in all stages of tumor formation, such as angiogenesis, invasion, migration, and proliferation. Due to their crucial roles in tumor formation and metastasis, chemokines and their receptors have garnered increasing interest in research on tumor recurrence, metastasis, and prognosis. This article reviewed the roles and functions of chemokines and their receptors in TME, as detailed in Table 3.

The role of chemokines in tumors

Chemotaxis and chemokine signaling to recruit different types of cells to the tumor, which helps shape the TME. The diverse roles of chemokine systems have been clarified by recent research, including immune cell recruitment, tumor cell proliferation and migration.

Chemokines promote immune evasion and immunosuppressive cell recruitment

Chemokines are pivotal in regulating immune cell migration and orchestrating immune responses against tumors (59). However, dysregulated chemokine expression in the TME can lead to the recruitment of immunomodulatory pro-tumor cells and promote cancer cell invasion. This includes TAMs, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Tregs are attracted by various chemokines, like the CCR6-CCL20 axis, which stimulates their proliferation and fosters tumor growth (60); TAMs hinder CD8⁺ T cell activation by suppressing tumor-associated antigens, thereby aiding tumor progression (61). Furthermore, TAMs induce monocyte differentiation into perivascular macrophages, contributing to vascular leakage and tumor endocytosis (62); MDSCs secrete chemokines like CCL3, CCL4, and CCL5, which suppress T and NK cells while promoting Treg recruitment. Additionally, MDSCs support tumor angiogenesis, metastasis, and epithelial-mesenchymal transition (EMT) (63); plasmacytoid DCs (pDCs) can also influence tumor immune response. For instance, the CXCL12/CXCR4 axis facilitates the emigration of pDCs to the TME, potentially promoting tumor emergence and progression (64). CXCL12 also aids in protecting pDCs from apoptosis within tumors (65).

Chemokines promote tumor cell progression and proliferation

Tumor growth is influenced by various factors, among which chemokines play a pivotal role (66). Chemokines generated by tumors, fibroblasts, and infiltrating leukocytes bind specifically to chemokine receptors on the surface of tumor cells, promoting the expression of cyclin D1 (67), Fos, and heparin-binding epidermal growth factor. This induction activates the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) signaling pathway, thereby enhancing tumor cell proliferation and survival. Additionally, chemokines downregulate Bcl-2 expression while upregulating anti-apoptotic gene expression (68). Previous research has demonstrated that CCL28 effectively inhibits cell apoptosis and stimulates breast cancer cell growth via MAPK/ERK-mediated anti-apoptosis and metastasis signaling pathways (69).

Chemokines promote angiogenesis

Malignant tumor development involves various processes, including local invasion, distant metastasis, clonal proliferation of altered cells, and malignant transformation. One critical process is tumor neovascularization. TAMs within the TME enhance angiogenesis and immunosuppress tumor cells, thereby facilitating tumor development, invasion, and migration. Chemokines act as essential mediators facilitating interaction between TAMs and tumor cells (70). Through chemokine secretion, TAMs accelerate tumor growth. Conversely, tumor-released chemokines mediate TAMs polarization and synthesis. Several chemokines and their receptors control TAMs recruitment, invasion, and polarization within the TME (71). TAMs, by the formation of angiogenic factors including vascular endothelial growth factor (VEGF) and TGF-β, stimulate tumor angiogenesis. Moreover, chemokines like CCL5 and CCL8 further facilitate tumor development and angiogenesis by recruiting and activating TAMs (72).

Chemokines promote tumor metastasis

Chemokine and their receptors may be vitally important for tumor metastasis, as connections between tumor and stromal cells in the TME often facilitate tumor spread through chemokine signaling. For instance, the CXCL12/CXCR4 axis activates signaling pathways with diverse effects on tumor cells proliferation, emigration, and gene expression, contributing to metastasis to the liver in colon cancer (73). This axis enables communication between stromal and tumor cells, promoting tumor development, survival, angiogenesis, and migration. Additionally, chemokines implicated in tumor metastasis, such as CCL28, which binds to CCR3, promote angiogenesis in lung adenocarcinomas by activating the MAPK/ERK signaling cascade. This implies that the CCL28/CCR3 axis mediates both the development and migration of lung cancer (74).

Application of chemokine targeting therapy in tumor immunity

Chemokines have impacts that are both pro- and anti-tumor and are pivotal in shaping the TME as mediators of immune cell trafficking. Moreover, chemokine receptors and chemokines can serve as trustworthy biomarkers for promptly detecting and diagnosing malignant tumors (13). This study focused on targeted chemokine receptors, including CXCR4, CXCR2, CCR5, CCR2, CCR1, and CCR6, as they are strongly associated with patient prognosis when expressed on immune cells and malignancies (Figure 2).

Figure 2 Mediating chemokine signaling of malignant tumors in the tumor microenvironment. Generated by Figdraw. The CXCR2/CXCL8 axis is capable of recruiting TANs, thereby stimulating tumor angiogenesis. The CCR1/CCL15 axis promotes the recruitment of MDSCs to tumor tissue through signal transduction. The CXCR4/CXCL12 axis can recruit dendritic cells and M2 macrophages, promoting the proliferation and growth of tumor cells. The CCR5/CCL5 axis can recruit Tregs and MDSCs, thereby promoting tumor cells proliferation, invasion, and migration. The CCR2/CCL2 axis can recruit Tregs, stimulating cancer cell proliferation and leading to migration and resistance to apoptosis. The CCR6/CCL20 axis helps regulate the infiltration of tumor-associated macrophages and stimulates cancer cell proliferation and migration. TANs, tumor-associated neutrophils; MDSCs, myeloid-derived suppressor cells.

The recruitment of DCs is significantly facilitated by CXCR4, thereby accelerating tumor cell proliferation and transformation. Activation of the CXCR4/CXCL12 axis stimulates various signaling pathways, like ERK1/2, Ras, p38 MAPK, and PLC/MAPK, promoting tumor cell invasion and distant migration, contributing to cancer cell transformation and progression (75,76). CXCR4 also regulates tumor angiogenesis and EMT, promoting the interaction between tumor and stromal cells (77). Inhibition of the CXCL12/CXCR4 axis significantly reduces M2 macrophage chemotaxis, potentially impeding tumor progression (78,79). Additionally, transmembrane glycoprotein CD248, present in many cancer and tumor stromal cells, facilitates M2 macrophage-induced secretion of CXCL12, promoting non-small cell lung cancer progression both in vivo and in vitro (80). Small molecule CXCR4 antagonist AMD3100 effectively inhibits gastrointestinal cancer cell invasion and metastasis by targeting CXCR4 (81), indicating that the CXCL12/CXCR4 axis may serve as a promising target for treating malignant tumors.

CXCR2, a major receptor for neutrophil trafficking, recruits TANs to the TME by the CXCR2/CXCL8 axis, stimulating tumor angiogenesis (82). CXCL8, a potent modulator of tumor angiogenesis promotes tumor microvessel growth and endothelial cell recruitment (83). Neutrophils permeate the tissue of tumors and subsequent production of angiogenic molecules like VEGF facilitates tumor vascularization upon CXCL8-induced CXCR2 activation (84). Recent research indicates that CXCR2 antagonists prevent colorectal cancer metastasis to the liver by enhancing cancer cell apoptosis and suppressing tumor angiogenesis in rat models (85).

CCR5 mediates the recruitment of immunosuppressive cells via multiple pathways, including Tregs and MDSCs, thus promoting tumor cell proliferation, invasion, and emigration (86). The CCL5/CCR5 axis exhibits oncogene-like functions, including tumor growth promotion, ECM remodeling, immunosuppressive cell recruitment, and MDSCs polarization (87,88). Furthermore, CCL5/CCR5 promotes TGF-β driven CD8⁺ CTL apoptosis and immunological escape by recruiting Tregs. Maraviroc, a small molecule inhibitor of CCR5 has been identified as an allosteric inverse agonist. In a mouse model of liver cancer, maraviroc decreases cell metastases to the body, bone, and brain by inhibiting the binding of CCL5 and CCR5, thus reducing cancer cell proliferation and metastasis (89).

CCR2 facilitates the migration of cancer cells and the recruitment of immune-suppressive cells into the TME through its interaction with CCL2 (90). Many studies have emphasized the important role of the CCL2/CCR2 axis in recruiting Tregs within the TME. Radiation therapy induces increased release of CCL2 from cancer cells, consequently activating CCR2 and promoting Treg recruitment in murine models of head and neck squamous cell carcinoma (91). RS504393, a specific CCR2 antagonist, inhibits immunosuppressive cell infiltration into the tumor cell site, thereby impeding tumor growth (92). This underscores the dependence of pro-tumor activation and immune evasion on the inhibitor RS504393, utilized to prevent CCR2 binding to its ligand CCL2.

CCR1, the first identified CC chemokine receptor, mediates the recruitment of MDSCs to malignant tumors through CCL15, promoting immune escape and disease progression (93). The CCL15/CCR1 axis facilitates MDSCs recruitment to tumor tissue through signal transduction (94). Antagonists of CCR1/CCL15 have demonstrated efficacy in reducing tumor burden, inhibiting metastasis, and slowing disease progression in multiple myeloma models (95). The therapeutic benefits of CCR1 targeting primarily stem from diminished MDSCs infiltration, thereby impeding tumor growth, metastasis, and disease advancement.

CCR6, in conjunction with CCL20, is found in several immune cell subtypes, including Th17 cells, Tregs, B cells, and DCs (96). CCL20 contributes to the genesis and development of lung and colorectal cancers, along with other conditions like rheumatoid arthritis and immunological responses (97). Prostate cancer progression is facilitated by the CCL20/CCR6 axis, which also promotes TAMs infiltration, M2 polarization, and CD163 expression in macrophages (98). CCL20 serves as a potential prognostic marker for chemotherapy resistance in tumor patients. Blocking CCL20 or its downstream molecules can reduce breast cancer stem cells, reverse chemotherapy resistance, and significantly enhance taxane treatment efficacy for breast cancer (99). Furthermore, cisplatin enhances ovarian cancer cell migration by activating macrophages and increasing CCL20 generation, leading to epithelial-to-mesenchymal transition through CCL20/CCR6 axis activation on ovarian cancer cells. Inhibiting the CCL20/CCR6 axis presents a promising treatment strategy to mitigate tumor cell migration induced by chemotherapy drugs.

TNFSF

The immune system is regulated by the TNFSF and its receptors (TNFRSF), which mediate the proliferation, survival, and development of immune cells. TNFSF is involved in the pathogenesis of numerous diseases, including autoimmune disorders, cancers, and development anomalies, while also contributing to both innate and adaptive immunity. Signaling pathways activated by TNFSF are implicated in both anti-tumor mechanisms such as apoptosis and pro-tumor actions like inflammation and cell survival. Various cytokines within TNFSF, such as TNF-α, CD137, and CD40, are involved in the formation, invasion, and migration.

Tumor necrosis factor α (TNF-α)

Predominantly secreted by macrophages, TNF-α is a crucial mediator of tumor-associated inflammation. It exhibits dual roles as an anti-tumorigenic cytokine and a pro-tumorigenic cytokine, that encourages angiogenesis, cell migration, proliferation, and disease development in a variety of tumor types (100). According to research, squamous cell carcinoma of the skin is significantly influenced by TNF-α. It is also generated as a proinflammatory cytokine in reaction to ultraviolet B radiation (UVB), promoting apoptosis, which aids in eliminating damaged cells and reduces the risk of tumor development (101). Moreover, TNF-α is necessary for squamous cell carcinogenesis and early stages of skin cancer (102). This suggests that TNF-α participates in immune responses that are both pro- and anti-tumor in cutaneous squamous cell carcinoma.

CD137

CD137 is a surface glycoprotein primarily produced by activated T lymphocytes and is a member of the tumor necrosis factor receptor family 9 (TNFRSF9). On activated DCs, CD137 binds to its native ligand CD137L (TNFSF9), promoting T cell proliferation and cytokine release while preventing T cell death. In numerous animal models, CD137 stimulates CD8⁺ T cell activation and proliferation of numerous tumor regressions (103). Therefore, CD137 represents a potential target for anti-tumor immunotherapy.

CD40

As a member of the TNFRSF cell surface family, CD40 is a co-stimulatory receptor. In contrast to other costimulatory targets, antigen-presenting cells (APCs), including DC cells, B cells, macrophages, and monocytes, are the primary sites of CD40 expression (104). CD40L, commonly referred to as CD154, is a transmembrane protein that is mostly produced by stimulated CD4⁺ T lymphocytes and is the sole ligand that interacts with CD40. CD40 agonists activate various immune cell types, enhancing the immune system’s anti-tumor response. T cells, particularly CTLs, are necessary for CD40 agonist-induced anti-tumor actions (105). Since antigen cross-presenting DCs is necessary for the anti-tumor effects of CD40 agonists in T cell-dependent models, DCs activation may be a key component of immunological response against tumors. Moreover, by delivering antigens to T cells and generating antibodies to target tumors, B cells stimulated by CD40 can strengthen the immune response against tumors (106).

Conclusions

Cytokine immunotherapy, as a cutting-edge science for the treatment of cancer, autoimmune disorders, and other diseases, constantly demonstrates its significance and promise. When conjunction with other treatment modalities including small compounds and monoclonal antibodies, therapeutic cytokines further contribute to modulating both innate and adaptive immune systems. While cytokines directly impact cancer cells, reports suggesting their role in tumor progression have been made; however, the prevailing view now considers them to predominantly exhibit anti-tumor actions. This article discusses the main functions of cytokines and chemokines in tumor immunotherapy, along with their potential applications in treating solid tumors. Particular attention is given to how these molecules target various cellular components of the TME, like DC cells, TAMs, and other immune cells. Interactions among tumor cells, immune cells, and cytokines constitute key aspects of the TME, providing a theoretical basis for targeting cytokine-mediated signaling pathways, directly and indirectly, to reshape tumor immune and biological phenotypes and enhance the therapeutic efficacy of immunotherapy. Nevertheless, there are certain challenges of cytokine immunotherapy, including high toxicity, brief half-life, and poor effectiveness. Limitations with anti-tumor cytokine therapy are currently being vigorously addressed through various technological platforms. In the future, studies on cytokines will focus on enhancing their efficiency and broaden their use to a wider variety of tumor types. Future endeavors concentrate on devising personalized treatment regimens, employing combination therapies, and conducting research and development of novel medications and therapeutic approaches. By thoroughly investigating the role of cytokines within the TME, we anticipate the development of more potent and precisely targeted immunotherapeutic medications, offering tumor patients with additional treatment options and hope.

Acknowledgments

Funding: This work was funded by the Joint Special Project of Basic Research of local undergraduate universities of Yunnan Province (Nos. 202001BA070001-064 and 202101BA070001-102) and the Open Project of Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D (No. AG2024002).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-679/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-679/coif). The authors have no conflicts of interest to declare.

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References

1. Babar Q, Saeed A, Tabish TA, et al. Targeting the tumor microenvironment: Potential strategy for cancer therapeutics. Biochim Biophys Acta Mol Basis Dis 2023;1869:166746. [Crossref] [PubMed]
2. Wu SY, Fu T, Jiang YZ, et al. Natural killer cells in cancer biology and therapy. Mol Cancer 2020;19:120. [Crossref] [PubMed]
3. de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023;41:374-403. [Crossref] [PubMed]
4. Essogmo FE, Zhilenkova AV, Tchawe YSN, et al. Cytokine Profile in Lung Cancer Patients: Anti-Tumor and Oncogenic Cytokines. Cancers (Basel) 2023;15:5383. [Crossref] [PubMed]
5. Look T, Puca E, Bühler M, et al. Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma. Sci Transl Med 2023;15:eadf2281. [Crossref] [PubMed]
6. Silver AB, Tzeng SY, Lager M, et al. An engineered immunocytokine with collagen affinity improves the tumor bioavailability, tolerability, and therapeutic efficacy of IL-2. Cell Rep Med 2023;4:101289. [Crossref] [PubMed]
7. Bhat AA, Nisar S, Singh M, et al. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022;42:689-715. [Crossref] [PubMed]
8. Anderson NM, Simon MC. The tumor microenvironment. Curr Biol 2020;30:R921-5. [Crossref] [PubMed]
9. Goenka A, Khan F, Verma B, et al. Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Commun (Lond) 2023;43:525-61. [Crossref] [PubMed]
10. Tiwari A, Trivedi R, Lin SY. Tumor microenvironment: barrier or opportunity towards effective cancer therapy. J Biomed Sci 2022;29:83. [Crossref] [PubMed]
11. Galli F, Aguilera JV, Palermo B, et al. Relevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy. J Exp Clin Cancer Res 2020;39:89. [Crossref] [PubMed]
12. Peppicelli S, Calorini L, Bianchini F, et al. Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells. Cell Oncol (Dordr) 2024; Epub ahead of print. [Crossref] [PubMed]
13. Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol 2022;19:237-53. [Crossref] [PubMed]
14. Gottschlich A, Endres S, Kobold S. Therapeutic Strategies for Targeting IL-1 in Cancer. Cancers (Basel) 2021;13:477. [Crossref] [PubMed]
15. Chang CP, Hu MH, Hsiao YP, et al. ST2 Signaling in the Tumor Microenvironment. Adv Exp Med Biol 2020;1240:83-93. [Crossref] [PubMed]
16. Zhou T, Damsky W, Weizman OE, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 2020;583:609-14. [Crossref] [PubMed]
17. Li M, Jiang W, Wang Z, et al. New insights on IL‑36 in intestinal inflammation and colorectal cancer Exp Ther Med 2023;25:275. (Review). [Crossref] [PubMed]
18. Damoiseaux J. The IL-2 - IL-2 receptor pathway in health and disease: The role of the soluble IL-2 receptor. Clin Immunol 2020;218:108515. [Crossref] [PubMed]
19. Kaiser FMP, Janowska I, Menafra R, et al. IL-7 receptor signaling drives human B-cell progenitor differentiation and expansion. Blood 2023;142:1113-30. [Crossref] [PubMed]
20. Waldmann TA. Cytokines in Cancer Immunotherapy. Cold Spring Harb Perspect Biol 2018;10:a028472. [Crossref] [PubMed]
21. Repici A, Ardizzone A, Filippone A, et al. Interleukin-21 Influences Glioblastoma Course: Biological Mechanisms and Therapeutic Potential. Cells 2023;12:2284. [Crossref] [PubMed]
22. Ouyang W, O'Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity 2019;50:871-91. [Crossref] [PubMed]
23. Smith S, Lopez S, Kim A, et al. Interleukin 24: Signal Transduction Pathways. Cancers (Basel) 2023;15:3365. [Crossref] [PubMed]
24. Hasegawa K, Tagawa M, Takagi K, et al. Anti-tumor immunity elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1. Cancer Gene Ther 2016;23:266-77. [Crossref] [PubMed]
25. Lee EHJ, Murad JP, Christian L, et al. Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Nat Commun 2023;14:4737. [Crossref] [PubMed]
26. Lin CH, Wu CJ, Cho S, et al. Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of T(H)17 cell immunity. Nat Immunol 2023;24:2108-20. [Crossref] [PubMed]
27. Mahfooz NS, Merling MR, Claeys TA, et al. Human IL-35 Inhibits the Bioactivity of IL-12 and Its Interaction with IL-12Rβ2. Immunohorizons 2023;7:431-41. [Crossref] [PubMed]
28. Váraljai R, Zimmer L, Al-Matary Y, et al. Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma. Nat Cancer 2023;4:1292-308. [Crossref] [PubMed]
29. Nie YJ, Wu SH, Xuan YH, et al. Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis. Mil Med Res 2022;9:21. [Crossref] [PubMed]
30. Leonard WJ, Lin JX. Strategies to therapeutically modulate cytokine action. Nat Rev Drug Discov 2023;22:827-54. [Crossref] [PubMed]
31. Niederlova V, Tsyklauri O, Kovar M, et al. IL-2-driven CD8(+) T cell phenotypes: implications for immunotherapy. Trends Immunol 2023;44:890-901. [Crossref] [PubMed]
32. Choudhry H, Helmi N, Abdulaal WH, et al. Prospects of IL-2 in Cancer Immunotherapy. Biomed Res Int 2018;2018:9056173. [Crossref] [PubMed]
33. Tannir NM, Formiga MN, Penkov K, et al. Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09). J Clin Oncol 2024;42:2800-11. [Crossref] [PubMed]
34. Hsu P, Santner-Nanan B, Hu M, et al. IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1. J Immunol 2015;195:3665-74. [Crossref] [PubMed]
35. Salkeni MA, Naing A. Interleukin-10 in cancer immunotherapy: from bench to bedside. Trends Cancer 2023;9:716-25. [Crossref] [PubMed]
36. Naing A, Papadopoulos KP, Autio KA, et al. Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors. J Clin Oncol 2016;34:3562-9. [Crossref] [PubMed]
37. Ma S, Caligiuri MA, Yu J. Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends Immunol 2022;43:833-47. [Crossref] [PubMed]
38. Margolin K, Morishima C, Velcheti V, et al. Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors. Clin Cancer Res 2018;24:5552-61. [Crossref] [PubMed]
39. Li Z, Yu X, Werner J, et al. The role of interleukin-18 in pancreatitis and pancreatic cancer. Cytokine Growth Factor Rev 2019;50:1-12. [Crossref] [PubMed]
40. Wu J, Zhang Q, Wu J, et al. IL-8 from CD248-expressing cancer-associated fibroblasts generates cisplatin resistance in non-small cell lung cancer. J Cell Mol Med 2024;28:e18185. [Crossref] [PubMed]
41. Zhai J, Shen J, Xie G, et al. Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer. Cancer Lett 2019;454:37-43. [Crossref] [PubMed]
42. Ren HM, Lukacher AE, Rahman ZSM, et al. New developments implicating IL-21 in autoimmune disease. J Autoimmun 2021;122:102689. [Crossref] [PubMed]
43. Chabab G, Bonnefoy N, Lafont V. IL-21 Signaling in the Tumor Microenvironment. Adv Exp Med Biol 2020;1240:73-82. [Crossref] [PubMed]
44. Li Y, Cong Y, Jia M, et al. Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy. Nat Commun 2021;12:951. [Crossref] [PubMed]
45. Kohli K, Pillarisetty VG, Kim TS. Key chemokines direct migration of immune cells in solid tumors. Cancer Gene Ther 2022;29:10-21. [Crossref] [PubMed]
46. Mempel TR, Lill JK, Altenburger LM. How chemokines organize the tumour microenvironment. Nat Rev Cancer 2024;24:28-50. [Crossref] [PubMed]
47. Amedei A, Prisco D, D' Elios MM. The use of cytokines and chemokines in the cancer immunotherapy. Recent Pat Anticancer Drug Discov 2013;8:126-42. [Crossref] [PubMed]
48. Raza S, Rajak S, Tewari A, et al. Multifaceted role of chemokines in solid tumors: From biology to therapy. Semin Cancer Biol 2022;86:1105-21. [Crossref] [PubMed]
49. Korbecki J, Kojder K, Simińska D, et al. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci 2020;21:8412. [Crossref] [PubMed]
50. Lin Y, Liu S, Sun Y, et al. CCR5 and inflammatory storm. Ageing Res Rev 2024;96:102286. [Crossref] [PubMed]
51. Korbecki J, Grochans S, Gutowska I, et al. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. Int J Mol Sci 2020;21:7619. [Crossref] [PubMed]
52. Liao J, Yu X, Huang Z, et al. Chemokines and lymphocyte homing in Sjögren's syndrome. Front Immunol 2024;15:1345381. [Crossref] [PubMed]
53. Mergia Terefe E, Catalan Opulencia MJ, Rakhshani A, et al. Roles of CCR10/CCL27-CCL28 axis in tumour development: mechanisms, diagnostic and therapeutic approaches, and perspectives. Expert Rev Mol Med 2022;24:e37. [Crossref] [PubMed]
54. Song N, Cui K, Zeng L, et al. Advance in the role of chemokines/chemokine receptors in carcinogenesis: Focus on pancreatic cancer. Eur J Pharmacol 2024;967:176357. [Crossref] [PubMed]
55. Korbecki J, Kupnicka P, Barczak K, et al. The Role of CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 Ligands in Molecular Cancer Processes and Clinical Aspects of Acute Myeloid Leukemia (AML). Cancers (Basel) 2023;15:4555. [Crossref] [PubMed]
56. Barbieri F, Bajetto A, Dellacasagrande I, et al. Stem-like signatures in human meningioma cells are under the control of CXCL11/CXCL12 chemokine activity. Neuro Oncol 2023;25:1775-87. [Crossref] [PubMed]
57. Szukiewicz D. CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis. Int J Mol Sci 2024;25:4679. [Crossref] [PubMed]
58. Heger L, Hatscher L, Liang C, et al. XCR1 expression distinguishes human conventional dendritic cell type 1 with full effector functions from their immediate precursors. Proc Natl Acad Sci U S A 2023;120:e2300343120. [Crossref] [PubMed]
59. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol 2019;16:356-71. [Crossref] [PubMed]
60. Ozga AJ, Chow MT, Luster AD. Chemokines and the immune response to cancer. Immunity 2021;54:859-74. [Crossref] [PubMed]
61. Zhou T, Qian H, Zhang D, et al. PGRN inhibits CD8(+)T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM. Cancer Immunol Immunother 2024;73:76. [Crossref] [PubMed]
62. Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 2017;17:559-72. [Crossref] [PubMed]
63. Li Z, Xia Q, He Y, et al. MDSCs in bone metastasis: Mechanisms and therapeutic potential. Cancer Lett 2024;592:216906. [Crossref] [PubMed]
64. Gallego C, Vétillard M, Calmette J, et al. CXCR4 signaling controls dendritic cell location and activation at steady state and in inflammation. Blood 2021;137:2770-84. [Crossref] [PubMed]
65. Kryczek I, Lange A, Mottram P, et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res 2005;65:465-72. [Crossref] [PubMed]
66. Do HTT, Lee CH, Cho J. Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers. Cancers (Basel) 2020;12:287. [Crossref] [PubMed]
67. Wei X, Pan S, Wang Z, et al. LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines. Cell Death Dis 2023;14:684. [Crossref] [PubMed]
68. Jiang T, Ma X, Chen H, et al. Diazepam ameliorated myocardial ischemia-reperfusion injury via inhibition of C-C chemokine receptor type 2/tumor necrosis factor-alpha/interleukins and Bcl-2-associated X protein/caspase-3 pathways in experimental rats. J Vet Med Sci 2021;83:1965-76. [Crossref] [PubMed]
69. Yang XL, Liu KY, Lin FJ, et al. CCL28 promotes breast cancer growth and metastasis through MAPK-mediated cellular anti-apoptosis and pro-metastasis. Oncol Rep 2017;38:1393-401. [Crossref] [PubMed]
70. Fu LQ, Du WL, Cai MH, et al. The roles of tumor-associated macrophages in tumor angiogenesis and metastasis. Cell Immunol 2020;353:104119. [Crossref] [PubMed]
71. Qin R, Ren W, Ya G, et al. Role of chemokines in the crosstalk between tumor and tumor-associated macrophages. Clin Exp Med 2023;23:1359-73. [Crossref] [PubMed]
72. Baci D, Bruno A, Cascini C, et al. Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies. J Exp Clin Cancer Res 2019;38:464. [Crossref] [PubMed]
73. Zhou W, Guo S, Liu M, et al. Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy. Curr Med Chem 2019;26:3026-41. [Crossref] [PubMed]
74. Huang G, Tao L, Shen S, et al. Hypoxia induced CCL28 promotes angiogenesis in lung adenocarcinoma by targeting CCR3 on endothelial cells. Sci Rep 2016;6:27152. [Crossref] [PubMed]
75. Mortezaee K. CXCL12/CXCR4 axis in the microenvironment of solid tumors: A critical mediator of metastasis. Life Sci 2020;249:117534. [Crossref] [PubMed]
76. Yang Y, Li J, Lei W, et al. CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications. Int J Biol Sci 2023;19:3341-59. [Crossref] [PubMed]
77. Mousavi A. CXCL12/CXCR4 signal transduction in diseases and its molecular approaches in targeted-therapy. Immunol Lett 2020;217:91-115. [Crossref] [PubMed]
78. Wang D, Wang X, Si M, et al. Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages. Cancer Lett 2020;474:36-52. [Crossref] [PubMed]
79. Sedighzadeh SS, Khoshbin AP, Razi S, et al. A narrative review of tumor-associated macrophages in lung cancer: regulation of macrophage polarization and therapeutic implications. Transl Lung Cancer Res 2021;10:1889-916. [Crossref] [PubMed]
80. Wu J, Liu X, Wu J, et al. CXCL12 derived from CD248-expressing cancer-associated fibroblasts mediates M2-polarized macrophages to promote nonsmall cell lung cancer progression. Biochim Biophys Acta Mol Basis Dis 2022;1868:166521. [Crossref] [PubMed]
81. Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol 2020;65:176-88. [Crossref] [PubMed]
82. Korbecki J, Kupnicka P, Chlubek M, et al. CXCR2 Receptor: Regulation of Expression, Signal Transduction, and Involvement in Cancer. Int J Mol Sci 2022;23:2168. [Crossref] [PubMed]
83. Asokan S, Bandapalli OR. CXCL8 Signaling in the Tumor Microenvironment. Adv Exp Med Biol 2021;1302:25-39. [Crossref] [PubMed]
84. Zhang M, Huang L, Ding G, et al. Interferon gamma inhibits CXCL8-CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer. J Immunother Cancer 2020;8:e000308. [Crossref] [PubMed]
85. Han ZJ, Li YB, Yang LX, et al. Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy. Molecules 2021;27:137. [Crossref] [PubMed]
86. Zeng Z, Lan T, Wei Y, et al. CCL5/CCR5 axis in human diseases and related treatments. Genes Dis 2022;9:12-27. [Crossref] [PubMed]
87. Liu J, Wang C, Ma X, et al. High expression of CCR5 in melanoma enhances epithelial-mesenchymal transition and metastasis via TGFβ1. J Pathol 2019;247:481-93. [Crossref] [PubMed]
88. Fattahi S, Amjadi-Moheb F, Tabaripour R, et al. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci 2020;262:118513. [Crossref] [PubMed]
89. Zhuang Y, Zhao X, Yuan B, et al. Blocking the CCL5-CCR5 Axis Using Maraviroc Promotes M1 Polarization of Macrophages Cocultured with Irradiated Hepatoma Cells. J Hepatocell Carcinoma 2021;8:599-611. [Crossref] [PubMed]
90. Pozzi S, Satchi-Fainaro R. The role of CCL2/CCR2 axis in cancer and inflammation: The next frontier in nanomedicine. Adv Drug Deliv Rev 2024;209:115318. [Crossref] [PubMed]
91. Mondini M, Loyher PL, Hamon P, et al. CCR2-Dependent Recruitment of Tregs and Monocytes Following Radiotherapy Is Associated with TNFα-Mediated Resistance. Cancer Immunol Res 2019;7:376-87. [Crossref] [PubMed]
92. Mu XY, Wang RJ, Yao ZX, et al. RS 504393 inhibits M-MDSCs recruiting in immune microenvironment of bladder cancer after gemcitabine treatment. Mol Immunol 2019;109:140-8. [Crossref] [PubMed]
93. Liu LZ, Zhang Z, Zheng BH, et al. CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma. Hepatology 2019;69:143-59. [Crossref] [PubMed]
94. Pang N, Lin Z, Wang X, et al. Endothelial cell‑derived CCL15 mediates the transmigration of fibrocytes through the CCL15‑CCR1 axis in vitro. Mol Med Rep 2020;22:5339-47. [Crossref] [PubMed]
95. Gilchrist A, Echeverria SL. Targeting Chemokine Receptor CCR1 as a Potential Therapeutic Approach for Multiple Myeloma. Front Endocrinol (Lausanne) 2022;13:846310. [Crossref] [PubMed]
96. Kadomoto S, Izumi K, Mizokami A. The CCL20-CCR6 Axis in Cancer Progression. Int J Mol Sci 2020;21:5186. [Crossref] [PubMed]
97. Chen W, Qin Y, Liu S. CCL20 Signaling in the Tumor Microenvironment. Adv Exp Med Biol 2020;1231:53-65. [Crossref] [PubMed]
98. Kano H, Izumi K, Hiratsuka K, et al. Suppression of androgen receptor signaling induces prostate cancer migration via activation of the CCL20-CCR6 axis. Cancer Sci 2023;114:1479-90. [Crossref] [PubMed]
99. Chen W, Qin Y, Wang D, et al. CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer. PLoS Biol 2018;16:e2005869. [Crossref] [PubMed]
100. Mercogliano MF, Bruni S, Mauro F, et al. Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy. Cancers (Basel) 2021;13:564. [Crossref] [PubMed]
101. Sharma MR, Mitrani R, Werth VP. Effect of TNFα blockade on UVB-induced inflammatory cell migration and collagen loss in mice. J Photochem Photobiol B 2020;213:112072. [Crossref] [PubMed]
102. Gubernatorova EO, Polinova AI, Petropavlovskiy MM, et al. Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice. Cancers (Basel) 2021;13:1775. [Crossref] [PubMed]
103. Pichler AC, Carrié N, Cuisinier M, et al. TCR-independent CD137 (4-1BB) signaling promotes CD8(+)-exhausted T cell proliferation and terminal differentiation. Immunity 2023;56:1631-1648.e10. [Crossref] [PubMed]
104. Li DK, Wang W. Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies. Oncol Lett 2020;20:176. [Crossref] [PubMed]
105. Enell Smith K, Deronic A, Hägerbrand K, et al. Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy. Expert Opin Biol Ther 2021;21:1635-46. [Crossref] [PubMed]
106. Salomon R, Dahan R. Next Generation CD40 Agonistic Antibodies for Cancer Immunotherapy. Front Immunol 2022;13:940674. [Crossref] [PubMed]