Chemokines bridge immune activation and tumor escape in radiotherapy

Abstract

Radiotherapy (RT) is a cancer treatment cornerstone, driving tumor cell death via DNA damage while simultaneously remodeling the tumor immune microenvironment (TME). Chemokines play a central role in this remodeling. They integrate diverse signals, including radiation-induced DNA damage, type I interferon, hypoxia, and senescence-associated secretory programs to direct immune-cell trafficking. However, RT-induced chemokine networks are not uniformly immunostimulatory or immunosuppressive. CXCL9/10/11-CXCR3 signaling generally promotes Th1, CD8⁺ T-cell, and NK-cell recruitment, whereas CCL2/5-CCR2/5 and CXCL12-CXCR4 frequently support myeloid-cell infiltration, stromal repair, vasculogenesis, and immune escape. Other axes, particularly CXCL8-CXCR1/2, display context-dependent effects that may either recruit suppressive myeloid cells or promote NK-cell-mediated tumor control after RT. In this review, we synthesize current evidence using a time-dose-context framework, emphasizing how tumor type, radiation dose and fractionation, post-RT timing, and tissue compartment determine chemokine function. We further evaluate therapeutic strategies that combine RT with chemokine-axis blockade and immune checkpoint inhibition, highlighting clinical barriers including biomarker selection, patient stratification, sequencing, and on-target/off-tumor toxicity. A more precise understanding of RT-induced chemokine dynamics may enable rational combination regimens that preserve immune activation while limiting compensatory tumor escape.

Keywords

Chemokines / Radiotherapy (RT) / Tumor immune microenvironment (TME) / Immune infiltration / Immunotherapy

References

[1] Almeida B, Lopes Rodrigues Amon R, Nogueira-Pedro A, Makiyama EN, Fock RA. In vitro impact of the radiation-induced bystander effect mediated by mesenchymal stem cells on leukemic cell migration: Implications for the CXCL12/CXCR4 axis. International Journal of Radiation Biology, 2025, 101(8): 835-845.

[2] Bahng I. CCR-CCL axes as key upstream influencers of pancreatic ductal adenocarcinoma: CCR2–CCL2, CCR5–CCL5, CCR4–CCL17/22, CCR6–CCL20, CCR7–CCL19/21. Frontiers in Immunology, 2026, 171713123

[3] Beach C, MacLean D, Majorova D, Arnold JN, Olcina MM. The effects of radiation therapy on the macrophage response in cancer. Frontiers in Oncology, 2022, 121020606

[4] Berchiche, Y. A., & Sakmar, T. P. (2016). CXC chemokine receptor 3 alternative splice variants selectively activate different signaling pathways. Molecular Pharmacology, 90(4), 483–495. https://doi.org/10.1124/mol.116.105502

[5] Bikfalvi A, Billottet C. The CC and CXC chemokines: Major regulators of tumor progression and the tumor microenvironment. American Journal of Physiology-Cell Physiology, 2020, 318(3): C542-C554.

[6] Boivin G, Kalambaden P, Faget J, Rusakiewicz S, Montay-Gruel P, Meylan E, Bourhis J, Lesec G, Vozenin M-C. Cellular composition and contribution of tertiary lymphoid structures to tumor immune infiltration and modulation by radiation therapy. Frontiers in Oncology, 2018, 8256

[7] Burnette B, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu Y-X, Auh SL. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Research, 2011, 71(7): 2488-2496.

[8] Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H., & Freeman, G. J. (2007). Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity, 27(1), 111–122. https://doi.org/10.1016/j.immuni.2007.05.016

[9] Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, Johansson I, Phung B, Harbst K, Vallon-Christersson J, van Schoiack A, Lövgren K, Warren S, Jirström K, Olsson H, Pietras K, Ingvar C, Isaksson K, Schadendorf D, Schmidt H, Bastholt L, Carneiro A, Wargo JA, Svane IM, Jönsson G. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature, 2020, 577(7791): 561-565.

[10] Cancilla D, Rettig MP, DiPersio JF. Targeting CXCR4 in AML and ALL. Frontiers in Oncology, 2020, 101672

[11] Cao T, Gu Y, Yagmurlu B, Yerraballa HP, Bertrand S, Naya L, Miller K, Iv M, Soltys SG, Patel CB, Nagpal S, Thomas RP, Brown M, Recht LD. A phase II study of plerixafor combined with whole brain radiation therapy (WBRT) for patients with newly diagnosed glioblastoma. Journal of Clinical Oncology, 2024, 42(16_suppl): 2075.

[12] Casagrande N, Borghese C, Visser L, Mongiat M, Colombatti A, Aldinucci D. CCR5 antagonism by maraviroc inhibits hodgkin lymphoma microenvironment interactions and xenograft growth. Haematologica, 2019, 104(3):564-575.

[13] Chaudary N, Hill RP, Milosevic M. Targeting the CXCL12/CXCR4 pathway to reduce radiation treatment side effects. Radiotherapy and Oncology, 2024, 194110194

[14] Chen J, Lin Q, Lan R, Wu J, Wang Z, Chen R, Huang W, Liu D, Yang Y, Hong J. A CCR5 antagonist enhances the radiosensitivity of hepatocarcinoma in a mouse model. Journal of Radiation Research, 2025, 66(4): 396-407.

[15] Cherney RJ, Anjanappa P, Selvakumar K, Batt DG, Brown GD, Rose AV, Vuppugalla R, Chen J, Pang J, Xu S, Yarde M, Tebben AJ, Paidi VR, Cvijic ME, Mathur A, Barrish JC, Mandlekar S, Zhao Q, Carter PH. BMS-813160: A potent CCR2 and CCR5 dual antagonist selected as a clinical candidate. ACS Medicinal Chemistry Letters, 2021, 12(11): 1753-1758.

[16] Chiang Y, Tsai Y-C, Wang C-C, Hsueh F-J, Huang C-Y, Chung S-D, Chen C-H, Pu Y-S, Cheng JC-H. Tumor-derived C-C motif ligand 2 induces the recruitment and polarization of tumor-associated macrophages and increases the metastatic potential of bladder cancer cells in the postirradiated microenvironment. International Journal of Radiation Oncology, Biology, Physics, 2022, 114(2): 321-333.

[17] Chiang Y, Lu L-F, Tsai C-L, Tsai Y-C, Wang C-C, Hsueh F-J, Huang C-Y, Chen C-H, Pu Y-S, Cheng J-H. C-C chemokine receptor 4 (CCR4)-positive regulatory T cells interact with tumor-associated macrophages to facilitate metastatic potential after radiation. European Journal of Cancer, 2024, 198113521

[18] Christenson E, Lim SJ, Wang H, Ferguson A, Parkinson R, Cetasaan Y, Rodriguez C, Burkhart R, De Jesus-Acosta A, He J, Klein RB, Lafaro K, Laheru D, Le DT, Shubert C, Zaidi N, Jaffee EM, Burns W, Narang A, Zheng L. Nivolumab and a CCR2/CCR5 dual antagonist (BMS-813160) with or without GVAX for locally advanced pancreatic ductal adenocarcinomas: Results of phase I study. Journal of Clinical Oncology, 2023, 41(4_suppl): 730.

[19] Colangelo, N. W., Gerber, N. K., Vatner, R. E., & Cooper, B. T. (2024). Harnessing the cGAS-STING pathway to potentiate radiation therapy: Current approaches and future directions. Frontiers in Pharmacology, 15, 1383000. https://doi.org/10.3389/fphar.2024.1383000

[20] Connolly KA, Belt BA, Figueroa NM, Murthy A, Patel A, Kim M, Lord EM, Linehan DC, Gerber SA. Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget, 2016, 7(52):86522-86535.

[21] Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Zou W. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine, 2004, 10(9): 942-949.

[22] Dai, J., Ma, L., Han, X., Li, X., Han, L., & Wang, W. (2026). Synergizing radiotherapy and immune checkpoint inhibitors in malignant solid tumours: Mechanistic insights and translational frontiers. Expert Reviews in Molecular Medicine, 28, e17. https://doi.org/10.1017/erm.2026.10041

[23] Davern M, O’ Donovan C, Donlon NE, Mylod E, Gaughan C, Bhardwaj A, Sheppard AD, Bracken-Clarke D, Butler C, Ravi N, Donohoe CL, Reynolds JV, Lysaght J, Conroy MJ. Analysing the combined effects of radiotherapy and chemokine receptor 5 antagonism: Complementary approaches to promote T cell function and migration in oesophageal adenocarcinoma. Biomedicines, 2024, 12(4819

[24] de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell, 2023, 413): 374-403.

[25] Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: Estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer, 2005, 104(6): 1129-1137.

[26] Derer A, Frey B, Fietkau R, Gaipl US. Immune-modulating properties of ionizing radiation: Rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunology, Immunotherapy, 2016, 65(7): 779-786.

[27] Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clinical Cancer Research, 2009, 15(17): 5379-5388.

[28] Dong F, Qin X, Wang B, Li Q, Hu J, Cheng X, Guo D, Cheng F, Fang C, Tan Y, Yan H, He Y, Sun X, Yuan Y, Liu H, Li T, Zhao Y, Kang C, Wu X. ALKBH5 facilitates hypoxia-induced paraspeckle assembly and IL8 secretion to generate an immunosuppressive tumor microenvironment. Cancer Research, 2021, 81(23): 5876-5888.

[29] Franciszkiewicz, K., Boissonnas, A., Boutet, M., Combadière, C., & Mami-Chouaib, F. (2012). Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response. Cancer Research, 72(24), 6325–6332. https://doi.org/10.1158/0008-5472.CAN-12-2027

[30] Frey B, Rückert M, Weber J, Mayr X, Derer A, Lotter M, Bert C, Rödel F, Fietkau R, Gaipl US. Hypofractionated irradiation has immune stimulatory potential and induces a timely restricted infiltration of immune cells in colon cancer tumors. Frontiers in Immunology, 2017, 8231

[31] García-López, M. A., Sánchez-Madrid, F., Rodríguez-Frade, J. M., Mellado, M., Acevedo, A., García, M. I., Albar, J. P., Martínez, C., & Marazuela, M. (2001). CXCR3 chemokine receptor distribution in normal and inflamed tissues: Expression on activated lymphocytes, endothelial cells, and dendritic cells. Laboratory Investigation, 81(3), 409–418. https://doi.org/10.1038/labinvest.3780248

[32] Giallongo, C., Dulcamare, I., Tibullo, D., Del Fabro, V., Vicario, N., Parrinello, N., Romano, A., Scandura, G., Lazzarino, G., Conticello, C., Li Volti, G., Amorini, A. M., Musumeci, G., Di Rosa, M., Polito, F., Oteri, R., Aguennouz, M., Parenti, R., Di Raimondo, F., & Palumbo, G. A. (2022). CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment. Oncogenesis, 11(1), 6. https://doi.org/10.1038/s41389-022-00380-z

[33] Giordano FA, Layer JP, Leonardelli S, Friker LL, Turiello R, Corvino D, Zeyen T, Schaub C, Müller W, Sperk E, Schmeel LC, Sahm K, Oster C, Kebir S, Hambsch P, Pietsch T, Bisdas S, Platten M, Glas M, Seidel C, Herrlinger U, Hölzel M. L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: Dose escalation of the phase I/II GLORIA trial. Nature Communications, 2024, 15(14210

[34] Groom JR, Luster AD. CXCR3 ligands: Redundant, collaborative and antagonistic functions. Immunology and Cell Biology, 2011, 892): 207-215.

[35] Guo C, Sharp A, Gurel B, Crespo M, Figueiredo I, Jain S, Vogl U, Rekowski J, Rouhifard M, Gallagher L, Yuan W, Carreira S, Chandran K, Paschalis A, Colombo I, Stathis A, Bertan C, Seed G, Goodall J, Raynaud F, Ruddle R, Swales KE, Malia J, Bogdan D, Tiu C, Caldwell R, Aversa C, Ferreira A, Neeb A, Tunariu N, Westaby D, Carmichael J, Fenor de la Maza MD, Yap C, Matthews R, Badham H, Prout T, Turner A, Parmar M, Tovey H, Riisnaes R, Flohr P, Gil J, Waugh D, Decordova S, Schlag A, Calì B, Alimonti A, de Bono JS. Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. Nature, 2023, 623(7989): 1053-1061.

[36] Haag GM, Springfeld C, Grün B, Apostolidis L, Zschäbitz S, Dietrich M, Berger A-K, Weber TF, Zoernig I, Schaaf M, Waberer L, Müller DW, Al-Batran S-E, Halama N, Jaeger D. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer—The PICCASSO phase I trial. European Journal of Cancer, 2022, 167: 112-122.

[37] Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell, 2011, 144(5): 646-674.

[38] Hassanian, H., Asadzadeh, Z., Baghbanzadeh, A., Derakhshani, A., Dufour, A., Rostami Khosroshahi, N., Najafi, S., Brunetti, O., Silvestris, N., & Baradaran, B. (2022). The expression pattern of Immune checkpoints after chemo/radiotherapy in the tumor microenvironment. Frontiers in Immunology, 13, 938063. https://doi.org/10.3389/fimmu.2022.938063

[39] Helmink, B. A., Reddy, S. M., Gao, J., Zhang, S., Basar, R., Thakur, R., Yizhak, K., Sade-Feldman, M., Blando, J., Han, G., Gopalakrishnan, V., Xi, Y., Zhao, H., Amaria, R. N., Tawbi, H. A., Cogdill, A. P., Liu, W., LeBleu, V. S., Kugeratski, F. G., Wargo, J. A. (2020). B cells and tertiary lymphoid structures promote immunotherapy response. Nature, 577(7791), 549–555. https://doi.org/10.1038/s41586-019-1922-8

[40] Hirata E, Sahai E. Tumor microenvironment and differential responses to therapy. Cold Spring Harbor Perspectives in Medicine, 2017, 7(7a026781

[41] Hu Q, Zuo X, Gu X, Liu L, Tang Y, Niu X, Shi Y, Han L. CXCL8 is essential for cervical cancer cell acquired radioresistance and acts as a promising therapeutic target in cervical cancer. Scientific Reports, 2025, 15120467

[42] Kai, K., Moriyama, M., Haque, A. S. M. R., Hattori, T., Chinju, A., Hu, C., Kubota, K., Miyahara, Y., Kakizoe-Ishiguro, N., Kawano, S., & Nakamura, S. (2021). Oral squamous cell carcinoma contributes to differentiation of monocyte-derived tumor-associated macrophages via PAI-1 and IL-8 production. International Journal of Molecular Sciences, 22(17), 9475. https://doi.org/10.3390/ijms22179475

[43] Kalbasi, A., Komar, C., Tooker, G. M., Liu, M., Lee, J. W., Gladney, W. L., Ben-Josef, E., & Beatty, G. L. (2017). Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clinical Cancer Research, 23(1), 137–148. https://doi.org/10.1158/1078-0432.CCR-16-0870

[44] Karapetyan, L., Iheagwara, U. K., Olson, A. C., Chmura, S. J., Skinner, H. K., & Luke, J. J. (2023). Radiation dose, schedule, and novel systemic targets for radio-immunotherapy combinations. JNCI: Journal of the National Cancer Institute, 115(11), 1278–1293. https://doi.org/10.1093/jnci/djad118

[45] Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. Journal of Clinical Investigation, 2010, 1203): 694-705.

[46] Kraske, J. A., Allers, M. M., Smirnov, A., Lenoir, B., Ahmed, A., Suarez-Carmona, M., Hampel, M., Krunic, D., Tietz-Dalfuß, A., Beikert, T., Schneeweiss, J. M., Brons, S., Albrecht, D., Trinh, T., Liu, M., Giese, N. A., Glowa, C., Liermann, J., Lopez Perez, R., Walle, T. (2025). Photon and particle radiotherapy induce redundant modular chemotaxis of human lymphocytes. JCI Insight, 10(18), e190149. https://doi.org/10.1172/jci.insight.190149

[47] Kuonen, F., Secondini, C., & Rüegg, C. (2012). Molecular pathways: Emerging pathways mediating growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment. Clinical Cancer Research, 18(19), 5196–5202. https://doi.org/10.1158/1078-0432.CCR-11-1758

[48] Le, D. T., Folprecht, G., Varghese, A. M., Gutierrez, M., Noel, M., Trikalinos, N. A., Chen, E., Dayyani, F., Davis, S. L., Ma, W. W., BasuMallick, A., Garrido-Laguna, I., Osawa, M., O’Brien, S., Novosiadly, R. D., Xu, K., Greenawalt, D. M., Dutta, S., Twyman Saint Victor, C., & Lenz, H.-J. (2026). Phase 1b/2 study of BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy or nivolumab in patients with advanced pancreatic or colorectal cancer. Journal for ImmunoTherapy of Cancer, 14(1), e011284. https://doi.org/10.1136/jitc-2024-011284

[49] Lecavalier-Barsoum, M., Chaudary, N., Han, K., Koritzinsky, M., Hill, R., & Milosevic, M. (2018). Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer. International Journal of Cancer, 143(5), 1017–1028. https://doi.org/10.1002/ijc.31297

[50] Letourneur, D., Danlos, F.-X., & Marabelle, A. (2020). Chemokine biology on immune checkpoint-targeted therapies. European Journal of Cancer, 137, 260–271. https://doi.org/10.1016/j.ejca.2020.06.009

[51] Lim, H. W., Hillsamer, P., & Kim, C. H. (2004). Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell–driven B cell responses. The Journal of Clinical Investigation, 114(11), 1640–1649. https://doi.org/10.1172/JCI22325

[52] Lin, C., He, H., Liu, H., Li, R., Chen, Y., Qi, Y., Jiang, Q., Chen, L., Zhang, P., Zhang, H., Li, H., Zhang, W., Sun, Y., & Xu, J. (2019). Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer. Gut, 68(10), 1764–1773. https://doi.org/10.1136/gutjnl-2018-316324

[53] Liu J, Yin T, Wu Y, Peng X, Zhang J, Zhan X. The dual role of the CXCL9/10/11-CXCR3 axis in the tumor immune microenvironment: Mechanisms, therapeutic implications, and clinical translation. Pharmacological Research, 2026, 229108254

[54] Liu, X., Lan, T., Mo, F., Yang, J., Wei, Y., & Wei, X. (2021). Antitumor and radiosensitization effects of a CXCR2 inhibitor in nasopharyngeal carcinoma. Frontiers in Cell and Developmental Biology, 9, 689613. https://doi.org/10.3389/fcell.2021.689613

[55] Liu, H., Yang, Z., Lu, W., Chen, Z., Chen, L., Han, S., Wu, X., Cai, T., & Cai, Y. (2020). Chemokines and chemokine receptors: A new strategy for breast cancer therapy. Cancer Medicine, 9(11), 3786–3799. https://doi.org/10.1002/cam4.3014

[56] Liu S, Wang W, Hu S, Jia B, Tuo B, Sun H, Wang Q, Liu Y, Sun Z. Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity. Cell Death & Disease, 2023, 14(10679

[57] Ma, J., Xin, Y., Wang, Q., & Ding, L. (2024). Roles of cGAS-STING pathway in radiotherapy combined with immunotherapy for hepatocellular carcinoma. Molecular Cancer Therapeutics, 23(4), 447–453. https://doi.org/10.1158/1535-7163.MCT-23-0373

[58] Manji, G. A., May, M. S., D’Souza, E. K., Pellicciotta, I., Sta Ana, S., Sender, N., Ross, I., Wang, S., Bates, S. E., Wu, L., Olive, K. P., Raufi, A. G., & Izar, B. (2025). CheMo4METPANC: Combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment-naïve pancreatic adenocarcinoma—updated clinical and translational findings. Journal of Clinical Oncology, 43(16_suppl), 4167. https://doi.org/10.1200/JCO.2025.43.16_suppl.4167

[59] Marcuzzi E, Angioni R, Molon B, Calì B. Chemokines and chemokine receptors: Orchestrating tumor metastasization. International Journal of Molecular Sciences, 2018, 20196

[60] Martinez-Zubiaurre, I., Chalmers, A. J., & Hellevik, T. (2018). Radiation-induced transformation of immunoregulatory networks in the tumor stroma. Frontiers in Immunology, 9, 1679. https://doi.org/10.3389/fimmu.2018.01679

[61] Matsumura, S., Wang, B., Kawashima, N., Braunstein, S., Badura, M., Cameron, T. O., Babb, J. S., Schneider, R. J., Formenti, S. C., Dustin, M. L., & Demaria, S. (2008). Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. The Journal of Immunology, 181(5), 3099–3107. https://doi.org/10.4049/jimmunol.181.5.3099

[62] Mondini, M., Loyher, P.-L., Hamon, P., Gerbé de Thoré, M., Laviron, M., Berthelot, K., Clémenson, C., Salomon, B. L., Combadière, C., Deutsch, E., & Boissonnas, A. (2019). CCR2-dependent recruitment of Tregs and monocytes following radiotherapy is associated with TNFα-mediated resistance. Cancer Immunology Research, 7(3), 376–387. https://doi.org/10.1158/2326-6066.CIR-18-0633

[63] Mortezaee, K. (2020). CXCL12/CXCR4 axis in the microenvironment of solid tumors: A critical mediator of metastasis. Life Sciences, 249, 117534. https://doi.org/10.1016/j.lfs.2020.117534

[64] Nagarsheth, N., Wicha, M. S., & Zou, W. (2017). Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nature Reviews Immunology, 17(9), 559–572. https://doi.org/10.1038/nri.2017.49

[65] Nie, G., Cao, X., Mao, Y., Lv, Z., Lv, M., Wang, Y., Wang, H., & Liu, C. (2021). Tumor-associated macrophages-mediated CXCL8 infiltration enhances breast cancer metastasis: Suppression by danirixin. International Immunopharmacology, 95, 107153. https://doi.org/10.1016/j.intimp.2020.107153

[66] Nywening, T. M., Wang-Gillam, A., Sanford, D. E., Belt, B. A., Panni, R. Z., Cusworth, B. M., Toriola, A. T., Nieman, R. K., Worley, L. A., Yano, M., Fowler, K. J., Lockhart, A. C., Suresh, R., Tan, B. R., Lim, K.-H., Fields, R. C., Strasberg, S. M., Hawkins, W. G., DeNardo, D. G., Linehan, D. C. (2016). Phase 1b study targeting tumour associated macrophages with CCR2 inhibition plus FOLFIRINOX in locally advanced and borderline resectable pancreatic cancer. The Lancet Oncology, 17(5), 651–662. https://doi.org/10.1016/S1470-2045(16)00078-4

[67] Obertopp, N., Bekker, R. A., Grass, G. D., Zelenka, T., Thomas, A., Potez, M., Ali, J., Blauvelt, J., Hall, A. M., Hall, M. S., Chung, C. H., Enderling, H., & Pilon-Thomas, S. (2025). Local single-dose radiation improves adoptive cell therapy with tumor-infiltrating lymphocytes. International Journal of Radiation Oncology, Biology, Physics, 123(4), 1102–1115. https://doi.org/10.1016/j.ijrobp.2025.06.3856

[68] Pan, M., Wei, X., Xiang, X., Liu, Y., Zhou, Q., & Yang, W. (2023). Targeting CXCL9/10/11–CXCR3 axis: An important component of tumor-promoting and antitumor immunity. Clinical and Translational Oncology, 25(8), 2306–2320. https://doi.org/10.1007/s12094-023-03126-4

[69] Pimenta, D. B., Varela, V. A., Datoguia, T. S., Caraciolo, V. B., Lopes, G. H., & Pereira, W. O. (2021). The bone marrow microenvironment mechanisms in acute myeloid leukemia. Frontiers in Cell and Developmental Biology, 9, 764698. https://doi.org/10.3389/fcell.2021.764698

[70] Png, S., Tadepalli, S., & Graves, E. E. (2025). Radiation-induced immune responses from the tumor microenvironment to systemic immunity. Cancers, 17(23), 3849. https://doi.org/10.3390/cancers17233849

[71] Pozzi, S., & Satchi-Fainaro, R. (2024). The role of CCL2/CCR2 axis in cancer and inflammation: The next frontier in nanomedicine. Advanced Drug Delivery Reviews, 209, 115318. https://doi.org/10.1016/j.addr.2024.115318

[72] Pun, N., Cytlak, U. M., Lee, D., Domingues, R. G., Cheadle, E. J., Forster, D., Whiteley, C., Honeychurch, J., Williams, K. J., Graham, G. J., Hepworth, M. R., Travis, M. A., Illidge, T. M., & Dyer, D. P. (2026). CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity. Mucosal Immunology, 19(1), 1509–1525. https://doi.org/10.1016/j.mucimm.2025.10.008

[73] Qin, R., Ren, W., Ya, G., Wang, B., He, J., Ren, S., Jiang, L., & Zhao, S. (2023). Role of chemokines in the crosstalk between tumor and tumor-associated macrophages. Clinical and Experimental Medicine, 23(5), 1359–1373. https://doi.org/10.1007/s10238-022-00888-z

[74] Rahimian, S., Najafi, H., & Doroudian, M. (2025). CXCR4-targeted theranostics in acute leukemia: Disrupting leukemic cell-microenvironment interactions with pentixafor and pentixather. Medical Oncology, 42(9), 402. https://doi.org/10.1007/s12032-025-02924-w

[75] Robinson MA, Kennedy A, Orozco CT, Chen H-C, Waters E, Giovacchini D, Yeung K, Filer L, Hinze C, Lloyd C, Dovedi SJ, Sansom DM. Rigid, bivalent CTLA-4 binding to CD80 is required to disrupt the cis CD80/PD-L1 interaction. Cell Reports, 2024, 439114768

[76] Sautès-Fridman, C., Petitprez, F., Calderaro, J., & Fridman, W. H. (2019). Tertiary lymphoid structures in the era of cancer immunotherapy. Nature Reviews Cancer, 19(6), 307–325. https://doi.org/10.1038/s41568-019-0144-6

[77] Shen, H., Jiang, Y., Wang, L., Hu, Z., Zhang, S., Cui, J., Shao, C., Li, C., Wang, Y., Lu, Z., & Huang, X. (2025). Jiawei Yanghe Decoction augments intratumoral CD8 + TIL infiltration and enhances radiotherapy efficacy in non-small cell lung cancer through CXCR3 ligand-mediated chemotaxis. Journal of Ethnopharmacology, 353, 120389. https://doi.org/10.1016/j.jep.2025.120389

[78] Singh DD, Yadav DK, Shin D. Targeting the CXCR4/CXCL12 axis to overcome drug resistance in triple-negative breast cancer. Cells, 2025, 14181482

[79] Spada, S., & Oweida, A. (2026). Combinatorial approaches for cancer immunotherapy. Cancer Immunology, Immunotherapy, 75(1), 34. https://doi.org/10.1007/s00262-025-04246-2

[80] Spranger, S., Bao, R., & Gajewski, T. F. (2015). Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature, 523(7559), 231–235. https://doi.org/10.1038/nature14404

[81] Thomas RP, Nagpal S, Iv M, Soltys SG, Bertrand S, Pelpola JS, Ball R, Yang J, Sundaram V, Lavezo J, Born D, Vogel H, Brown JM, Recht LD. Macrophage exclusion after radiation therapy (MERT): A first in human phase I/II trial using a CXCR4 inhibitor in glioblastoma. Clinical Cancer Research, 2019, 2523): 6948-6957.

[82] Tian, S., Liu, J., Yang, X., & Guo, J. (2026). The CXCL12-CXCR4 axis in colorectal cancer: Immune regulation, metastatic progression, and therapeutic implications. Frontiers in Immunology, 17, 1783222. https://doi.org/10.3389/fimmu.2026.1783222

[83] Totis C, Averbeck NB, Jakob B, Schork M, Volpi G, Hintze DF, Durante M, Fournier C, Helm A. Induction of cytoplasmic dsDNA and cGAS-STING immune signaling after exposure of breast cancer cells to X-ray or high-energetic carbon ions. Advances in Radiation Oncology, 2025, 10(6101783

[84] Tu, M. M., Abdel-Hafiz, H. A., Jones, R. T., Jean, A., Hoff, K. J., Duex, J. E., Chauca-Diaz, A., Costello, J. C., Dancik, G. M., Tamburini, B. A. J., Czerniak, B., Kaye, J., & Theodorescu, D. (2020). Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy. Communications Biology, 3(1), 720. https://doi.org/10.1038/s42003-020-01441-y

[85] Vanpouille-Box, C., Alard, A., Aryankalayil, M. J., Sarfraz, Y., Diamond, J. M., Schneider, R. J., Inghirami, G., Coleman, C. N., Formenti, S. C., & Demaria, S. (2017). DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nature Communications, 8, 15618. https://doi.org/10.1038/ncomms15618

[86] Walle T, Kraske JA, Liao B, Lenoir B, Timke C, von Bohlen Und Halbach E, Tran F, Griebel P, Albrecht D, Ahmed A, Suarez-Carmona M, Jiménez-Sánchez A, Beikert T, Tietz-Dahlfuß A, Menevse AN, Schmidt G, Brom M, Pahl JHW, Antonopoulos W, Miller M, Perez RL, Bestvater F, Giese NA, Beckhove P, Rosenstiel P, Jäger D, Strobel O, Pe’er D, Halama N, Debus J, Cerwenka A, Huber PE. Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8. Science Advances, 2022, 812eabh4050

[87] Wang J, Saung MT, Li K, Fu J, Fujiwara K, Niu N, Muth S, Wang J, Xu Y, Rozich N, Zlomke H, Chen S, Espinoza B, Henderson M, Funes V, Herbst B, Ding D, Twyman-Saint Victor C, Zhao Q, Henderson MK, Narang A, He J, Zheng L. CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma. Journal of Experimental Medicine, 2022, 2195e20211631

[88] Wang, L., Jiang, J., Chen, Y., Jia, Q., & Chu, Q. (2022b). The roles of CC chemokines in response to radiation. Radiation Oncology, 17(1), 63. https://doi.org/10.1186/s13014-022-02038-x

[89] Wang, X. X., Zhu, C., Sun, Y., Xie, X., Wang, M., Jin, Y., Gu, Y., Qian, L., Shi, L., Xu, J., Wang, F., Huang, X., Dai, S., & Sun, X. (2026). Modulating the tumor immune phenotypes by radiotherapy: Formulating and validating the combination therapy of radiation, PD-L1, and TIM-3 blockade in colorectal cancer. Journal for ImmunoTherapy of Cancer, 14(2), e013656. https://doi.org/10.1136/jitc-2025-013656

[90] Wei, S., Kryczek, I., & Zou, W. (2006). Regulatory T-cell compartmentalization and trafficking. Blood, 108(2), 426–431. https://doi.org/10.1182/blood-2006-01-0177

[91] Weichselbaum RR, Liang H, Deng L, Fu Y-X. Radiotherapy and immunotherapy: A beneficial liaison?. Nature Reviews Clinical Oncology, 2017, 146): 365-379.

[92] Wu, Y., Song, Y., Wang, R., & Wang, T. (2023). Molecular mechanisms of tumor resistance to radiotherapy. Molecular Cancer, 22, 96. https://doi.org/10.1186/s12943-023-01801-2

[93] Xavier, H., Gireesh, A. G. M., Thomas, J. A., Suboj, P., Suresh, A., Biju, E., Baby, A., Dominic, R. T., & Babykutty, S. (2025). Chemokines: Humble yet mighty players in the tumour microenvironment. Frontiers in Immunology, 16, 1601756. https://doi.org/10.3389/fimmu.2025.1601756

[94] Xu, Y., Chen, J., Qiu, Y., & Du, J. (2025). Radiotherapy and immune microenvironment crosstalk in pancreatic cancer: A comprehensive review of current insights and future directions. Frontiers in Immunology, 16, 1619946. https://doi.org/10.3389/fimmu.2025.1619946

[95] Yi, M., Li, T., Niu, M., Zhang, H., Wu, Y., Wu, K., & Dai, Z. (2024). Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduction and Targeted Therapy, 9(1), 176. https://doi.org/10.1038/s41392-024-01868-3

[96] Zhang, C., Zhou, Y., Gao, Y., Zhu, Z., Zeng, X., Liang, W., Sun, S., Chen, X., & Wang, H. (2022a). Radiated glioblastoma cell-derived exosomal circ_0012381 induce M2 polarization of microglia to promote the growth of glioblastoma by CCL2/CCR2 axis. Journal of Translational Medicine, 20, 388. https://doi.org/10.1186/s12967-022-03607-0

[97] Zhang Z, Liu X, Chen D, Yu J. Radiotherapy combined with immunotherapy: The dawn of cancer treatment. Signal Transduction and Targeted Therapy, 2022, 7258

[98] Zhang, Y., Fan, B., Yang, H., Chen, G., Huang, Z., Li, Y., Ma, X., Wang, T., Wang, W., Cai, L., Han, L., Liu, Y., Li, D., Chen, X., Yang, Y., & Yang, Z. (2025). CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review). Oncology Letters, 30(6), 598. https://doi.org/10.3892/ol.2025.15344

[99] Zhao, Y., Wang, X., Lei, T., Lu, H., Zhao, Y., & Wang, G. (2026). Chemokine-chemokine receptor axis: Emerging immunotherapeutic paradigms for solid tumor microenvironment reprogramming. Chinese Medical Journal, 139(8), 1125–1148. https://doi.org/10.1097/CM9.0000000000004009

[100] Zheng, W., Ling, S., Cao, Y., Shao, C., & Sun, X. (2024). Combined use of NK cells and radiotherapy in the treatment of solid tumors. Frontiers in Immunology, 14, 1306534. https://doi.org/10.3389/fimmu.2023.1306534

[101] Zhou, M., Chen, M., Shi, B., Di, S., Sun, R., Jiang, H., & Li, Z. (2022). Radiation enhances the efficacy of EGFR-targeted CAR-T cells against triple-negative breast cancer by activating NF-κB/Icam1 signaling. Molecular Therapy, 30(11), 3379–3393. https://doi.org/10.1016/j.ymthe.2022.07.021

[102] Zlotnik, A., & Yoshie, O. (2012). The chemokine superfamily revisited. Immunity, 36(5), 705–716. https://doi.org/10.1016/j.immuni.2012.05.008

Funding

National Natural Science Foundation of China(82373212)

Shenzhen Science and Technology Innovation Program(JCYJ20240813142112017)

Rights & permissions

Shenzhen University Medical School