Immunotherapy has revolutionized the clinical management of many malignancies but is infrequently associated with durable objective responses when used as a standalone treatment approach, calling for the development of combinatorial regimens with superior efficacy and acceptable toxicity. Radiotherapy, the most commonly used oncological treatment, has attracted considerable attention as a combination partner for immunotherapy owing to its well-known and predictable safety profile, widespread clinical availability, and potential for immunostimulatory effects. However, numerous randomized clinical trials investigating radiotherapy–immunotherapy combinations have failed to demonstrate a therapeutic benefit compared with either modality alone. Such a lack of interaction might reflect suboptimal study design, choice of end points and/or administration of radiotherapy according to standard schedules and target volumes. Indeed, radiotherapy has empirically evolved towards radiation doses and fields that enable maximal cancer cell killing with manageable toxicity to healthy tissues, without much consideration of potential radiation-induced immunostimulatory effects. Herein, we propose the concept that successful radiotherapy–immunotherapy combinations might require modifications of standard radiotherapy regimens and target volumes to optimally sustain immune fitness and enhance the antitumour immune response in support of meaningful clinical benefits.
Numerous clinical studies investigating radiotherapy as a combination partner for immunotherapies, particularly immune-checkpoint inhibitors, failed to reveal a therapeutic benefit over either treatment modality alone.
In this context, radiotherapy has often been applied according to conventional regimens and/or target volumes, with limited consideration for potential radiotherapy-driven immunomodulation.
Conventional radiation doses and fractionation schedules might result in robust immunosuppression in the tumour microenvironment, at least in part reflecting the repeated killing of circulating immune effector cells.
Conventional radiotherapy target volumes are also expected to exacerbate local and systemic immunosuppression given that they often include tumour-draining lymph nodes (which are key sites for the initiation of anticancer immunity) and circulating immune cells.
Multiple cellular alterations elicited by radiotherapy are temporally dynamic, suggesting that the treatment schedule (relative timing and sequencing) is a major determinant of the efficacy of radiotherapy–immunotherapy combinations.
We surmise that improved radiotherapy regimens and target volumes might enable the development of radiotherapy–immunotherapy combinations with superior clinical activity, at least in some patient populations.
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Sharma, P. et al. The next decade of immune checkpoint therapy. Cancer Discov. 11, 838–857 (2021).
Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/s41571-023-00754-1 (2023).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Mishima, S. et al. Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition. Int. J. Clin. Oncol. 25, 217–239 (2020).
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
Verma, V. Economic sustainability of immune-checkpoint inhibitors: the looming threat. Nat. Rev. Clin. Oncol. 15, 721–722 (2018).
Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).
Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).
Demaria, S., Bhardwaj, N., McBride, W. H. & Formenti, S. C. Combining radiotherapy and immunotherapy: a revived partnership. Int. J. Radiat. Oncol. Biol. Phys. 63, 655–666 (2005).
Formenti, S. C. & Demaria, S. Future of radiation and immunotherapy. Int. J. Radiat. Oncol. Biol. Phys. 108, 3–5 (2020).
Pointer, K. B., Pitroda, S. P. & Weichselbaum, R. R. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer 8, 9–20 (2022).
De Ruysscher, D. et al. Radiotherapy toxicity. Nat. Rev. Dis. Prim. 5, 13 (2019).
Sullivan, R. J. & Weber, J. S. Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies. Nat. Rev. Drug Discov. 21, 495–508 (2022).
Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).
Bates, J. E., Sanders, T., Arnone, A., Elmore, S. N. C. & Royce, T. J. Geographic density of linear accelerators and receipt of radiation therapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 111, e351–e352 (2021).
Golden, E. B. & Formenti, S. C. Is tumor (R)ejection by the immune system the “5th R” of radiobiology? Oncoimmunology 3, e28133 (2014).
Rodriguez-Ruiz, M. E., Vitale, I., Harrington, K. J., Melero, I. & Galluzzi, L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat. Immunol. 21, 120–134 (2020).
McLaughlin, M. et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer 20, 203–217 (2020).
Cytlak, U. M. et al. Immunomodulation by radiotherapy in tumour control and normal tissue toxicity. Nat. Rev. Immunol. 22, 124–138 (2022).
Paix, A. et al. Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: a review. Crit. Rev. Oncol. Hematol. 123, 138–148 (2018).
Golden, E. B., Marciscano, A. E. & Formenti, S. C. Radiation therapy and the in situ vaccination approach. Int. J. Radiat. Oncol. Biol. Phys. 108, 891–898 (2020).
Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).
Newcomb, E. W. et al. The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin. Cancer Res. 12, 4730–4737 (2006).
Lhuillier, C. et al. Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control. J. Clin. Invest. 131, e138740 (2021).
Golden, E. B. et al. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 3, e28518 (2014).
Zhou, H. et al. Carbon ion radiotherapy triggers immunogenic cell death and sensitizes melanoma to anti-PD-1 therapy in mice. Oncoimmunology 11, 2057892 (2022).
Burnette, B. C. et al. The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res. 71, 2488–2496 (2011).
Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).
Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).
Yamazaki, T. et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat. Immunol. 21, 1160–1171 (2020).
Rodríguez-Ruiz, M. E. et al. TGFβ blockade enhances radiotherapy abscopal efficacy effects in combination with anti-PD1 and anti-CD137 immunostimulatory monoclonal antibodies. Mol. Cancer Ther. 18, 621–631 (2019).
Rodriguez-Ruiz, M. E. et al. Abscopal effects of radiotherapy are enhanced by combined immunostimulatory mAbs and are dependent on CD8 T cells and crosspriming. Cancer Res. 76, 5994–6005 (2016).
Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).
DeSelm, C. et al. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol. Ther. 26, 2542–2552 (2018).
Yamazaki, T. et al. LTX-315-enabled, radiotherapy-boosted immunotherapeutic control of breast cancer by NK cells. Oncoimmunology 10, 1962592 (2021).
Laurent, P. A., Morel, D., Meziani, L., Depil, S. & Deutsch, E. Radiotherapy as a means to increase the efficacy of T-cell therapy in solid tumors. Oncoimmunology 12, 2158013 (2023).
Pilones, K. A. et al. Radiotherapy cooperates with IL15 to induce antitumor immune responses. Cancer Immunol. Res. 8, 1054–1063 (2020).
Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018).
Zhou, Q. et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 23, 209–219 (2022).
Altorki, N. K. et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. Lancet Oncol. 22, 824–835 (2021).
Kelly, R. J. et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N. Engl. J. Med. 384, 1191–1203 (2021).
Formenti, S. C. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24, 1845–1851 (2018).
Lim, M. et al. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro-Oncology 24, 1935–1949 (2022).
Omuro, A. et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial. Neuro-Oncology 25, 123–134 (2023).
Lee, N. Y. et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 22, 450–462 (2021).
Bourhis, J. et al. Avelumab-cetuximab-radiotherapy versus standards of care in patients with locally advanced squamous cell carcinoma of head and neck (LA-SCCHN): randomized phase III GORTEC-REACH trial. Ann. Oncol. 32, S1310–S1310 (2021).
Lo, S. S. et al. Stereotactic body radiation therapy: a novel treatment modality. Nat. Rev. Clin. Oncol. 7, 44–54 (2010).
Prasanna, A., Ahmed, M. M., Mohiuddin, M. & Coleman, C. N. Exploiting sensitization windows of opportunity in hyper and hypo-fractionated radiation therapy. J. Thorac. Dis. 6, 287–302 (2014).
Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).
Jayaprakash, P. et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J. Clin. Invest. 128, 5137–5149 (2018).
Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6Chigh monocytes. Cancer Res. 70, 5728–5739 (2010).
Wenes, M. et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 24, 701–715 (2016).
Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).
Vignali, P. D. A. et al. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat. Immunol. 24, 267–279 (2022).
Suthen, S. et al. Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology 76, 1329–1344 (2022).
Park, J. H. et al. Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors. Nat. Immunol. 22, 336–346 (2021).
Sethumadhavan, S. et al. Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells. PLoS ONE 12, e0187314 (2017).
Baginska, J. et al. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl Acad. Sci. USA 110, 17450–17455 (2013).
Monjazeb, A. M. et al. A randomized trial of combined PD-L1 and CTLA-4 inhibition with targeted low-dose or hypofractionated radiation for patients with metastatic colorectal cancer. Clin. Cancer Res. 27, 2470–2480 (2021).
Yovino, S., Kleinberg, L., Grossman, S. A., Narayanan, M. & Ford, E. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest. 31, 140–144 (2013).
Wild, A. T. et al. Lymphocyte-sparing effect of stereotactic body radiation therapy in patients with unresectable pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 94, 571–579 (2016).
Tang, C. et al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int. J. Radiat. Oncol. Biol. Phys. 89, 1084–1091 (2014).
Luke, J. J. et al. Improved survival associated with local tumor response following multisite radiotherapy and pembrolizumab: secondary analysis of a phase I trial. Clin. Cancer Res. 26, 6437–6444 (2020).
Rodriguez-Ruiz, M. E. et al. Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients. Oncoimmunology 8, e1655964 (2019).
Ning, X. et al. Apoptotic caspases suppress type I interferon production via the cleavage of cGAS, MAVS, and IRF3. Mol. Cell 74, 19–31.e7 (2019).
Marchi, S., Guilbaud, E., Tait, S. W. G., Yamazaki, T. & Galluzzi, L. Mitochondrial control of inflammation. Nat. Rev. Immunol. 23, 159–173 (2022).
Klug, F. et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24, 589–602 (2013).
Herrera, F. G. et al. Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy. Cancer Discov. 12, 108–133 (2022).
Barsoumian, H. B. et al. Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma. J. Immunother. Cancer 8, e000537 (2020).
Yin, L. et al. Effect of low-dose radiation therapy on abscopal responses to hypofractionated radiation therapy and anti-PD1 in mice and patients with non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 108, 212–224 (2020).
Schoenfeld, J. D. et al. Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 23, 279–291 (2022).
Chang, J. Y., Verma, V., Welsh, J. W. & Formenti, S. C. Radiotherapy plus immune checkpoint blockade in PD(L)-1-resistant metastatic NSCLC. Lancet Oncol. 23, e156 (2022).
Patel, R. R. et al. High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: results of a phase II trial. Radiother. Oncol. 162, 60–67 (2021).
Theelen, W. et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol. 5, 1276–1282 (2019).
McBride, S. et al. Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma. J. Clin. Oncol. 39, 30–37 (2021).
De Meerleer, G. et al. Elective nodal radiotherapy in prostate cancer. Lancet Oncol. 22, e348–e357 (2021).
Cramer, J. D., Burtness, B., Le, Q. T. & Ferris, R. L. The changing therapeutic landscape of head and neck cancer. Nat. Rev. Clin. Oncol. 16, 669–683 (2019).
Huang, Q. et al. The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell 185, 4049–4066.e25 (2022).
Prokhnevska, N. et al. CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor. Immunity 56, 107–124.e5 (2023).
Marciscano, A. E. et al. Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy. Clin. Cancer Res. 24, 5058–5071 (2018).
Buchwald, Z. S. et al. Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy. J. Immunother. Cancer 8, e000867 (2020).
Saddawi-Konefka, R. et al. Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC. Nat. Commun. 13, 4298 (2022).
Darragh, L. B. et al. Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors. Nat. Commun. 13, 7015 (2022).
Leidner, R. et al. Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma. J. Immunother. Cancer 9, e002485 (2021).
Trowell, O. A. The sensitivity of lymphocytes to ionising radiation. J. Pathol. Bacteriol. 64, 687–704 (1952).
Arina, A. et al. Tumor-reprogrammed resident T cells resist radiation to control tumors. Nat. Commun. 10, 3959 (2019).
Lee, S. F. et al. Splenic irradiation contributes to grade ≥ 3 lymphopenia after adjuvant chemoradiation for stomach cancer. Clin. Transl. Radiat. Oncol. 36, 83–90 (2022).
Sakaguchi, M., Maebayashi, T., Aizawa, T., Ishibashi, N. & Okada, M. Association between unintentional splenic radiation and lymphopenia and high neutrophil/lymphocyte ratio after radiotherapy in patients with esophageal cancer. Transl. Cancer Res. 10, 5076–5084 (2021).
Reddy, A. V. et al. Vertebral body and splenic irradiation are associated with lymphopenia in localized pancreatic cancer treated with stereotactic body radiation therapy. Radiat. Oncol. 16, 242 (2021).
Nakamura, N., Kusunoki, Y. & Akiyama, M. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay. Radiat. Res. 123, 224–227 (1990).
Reddy, A. V. et al. Post-radiation neutrophil-to-lymphocyte ratio is a prognostic marker in patients with localized pancreatic adenocarcinoma treated with anti-PD-1 antibody and stereotactic body radiation therapy. Radiat. Oncol. J. 40, 111–119 (2022).
Chen, D. et al. Absolute lymphocyte count predicts abscopal responses and outcomes in patients receiving combined immunotherapy and radiation therapy: analysis of 3 phase 1/2 trials. Int. J. Radiat. Oncol. Biol. Phys. 108, 196–203 (2020).
Punjabi, A. et al. Neutrophil-lymphocyte ratio and absolute lymphocyte count as prognostic markers in patients treated with curative-intent radiotherapy for non-small cell lung cancer. Clin. Oncol. 33, e331–e338 (2021).
MacDougall, K., Niazi, M. R. K., Hosry, J., Homsy, S. & Bershadskiy, A. The prognostic significance of peripheral blood biomarkers in patients with advanced non-small cell lung cancer treated with pembrolizumab: a clinical study. Oncology 36, 156–161 (2022).
D’Auria, F. et al. Modulation of peripheral immune cell subpopulations after rapidArc/moderate hypofractionated radiotherapy for localized prostate cancer: findings and comparison with 3D conformal/conventional fractionation treatment. Front. Oncol. 12, 829812 (2022).
Mohan, R. et al. Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons. Neuro-Oncology 23, 284–294 (2021).
Venkatesulu, B. P. et al. Ultra high dose rate (35 Gy/sec) radiation does not spare the normal tissue in cardiac and splenic models of lymphopenia and gastrointestinal syndrome. Sci. Rep. 9, 17180 (2019).
Iturri, L. et al. Proton FLASH radiation therapy and immune infiltration: evaluation in an orthotopic glioma rat model. Int. J. Radiat. Oncol. Biol. Phys. https://doi.org/10.1016/j.ijrobp.2022.12.018 (2022).
Montay-Gruel, P. et al. Hypofractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side effects in mice. Clin. Cancer Res. 27, 775–784 (2021).
Favaudon, V. et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6, 245ra293 (2014).
Moding, E. J., Kastan, M. B. & Kirsch, D. G. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat. Rev. Drug Discov. 12, 526–542 (2013).
Fogliata, A. et al. Collimator scatter factor: Monte Carlo and in-air measurements approaches. Radiat. Oncol. 13, 126 (2018).
Khan, R., Gul, B., Khan, S., Nisar, H. & Ahmad, I. Refractive index of biological tissues: review, measurement techniques, and applications. Photodiagnosis Photodyn. Ther. 33, 102192 (2021).
Wang, K. K. & Zhu, T. C. Modeling scatter-to-primary dose ratio for megavoltage photon beams. Med. Phys. 37, 5270–5278 (2010).
Westermann, W., Schöbl, R., Rieber, E. P. & Frank, K. H. Th2 cells as effectors in postirradiation pulmonary damage preceding fibrosis in the rat. Int. J. Radiat. Biol. 75, 629–638 (1999).
Wirsdorfer, F. et al. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells. Radiat. Oncol. 9, 98 (2014).
Xiong, S. et al. Treg depletion attenuates irradiation-induced pulmonary fibrosis by reducing fibrocyte accumulation, inducing Th17 response, and shifting IFN-γ, IL-12/IL-4, IL-5 balance. Immunobiology 220, 1284–1291 (2015).
Xiong, S. et al. Regulatory T cells promote β-catenin-mediated epithelium-to-mesenchyme transition during radiation-induced pulmonary fibrosis. Int. J. Radiat. Oncol. Biol. Phys. 93, 425–435 (2015).
Park, H. R., Jo, S. K. & Jung, U. Ionizing radiation promotes epithelial-to-mesenchymal transition in lung epithelial cells by TGF-β-producing M2 macrophages. Vivo 33, 1773–1784 (2019).
Puthawala, K. et al. Inhibition of integrin αvβ6, an activator of latent transforming growth factor-β, prevents radiation-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 177, 82–90 (2008).
Meyer, J. E. et al. Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation. Cell Cycle 16, 1171–1174 (2017).
Zhang, P. et al. Local tumor control and normal tissue toxicity of pulsed low-dose rate radiotherapy for recurrent lung cancer: an in vivo animal study. Dose Response 13, 1559325815588507 (2015).
Myers, C. J. & Lu, B. Decreased survival after combining thoracic irradiation and an anti-PD-1 antibody correlated with increased T-cell infiltration into cardiac and lung tissues. Int. J. Radiat. Oncol. Biol. Phys. 99, 1129–1136 (2017).
Schlaak, R. A. et al. Acquired immunity is not essential for radiation-induced heart dysfunction but exerts a complex impact on injury. Cancers 12, 983 (2020).
Lenarczyk, M. et al. T cells contribute to pathological responses in the non-targeted rat heart following irradiation of the kidneys. Toxics 10, 797 (2022).
Beschel, L. M. et al. T cell abundance in blood predicts acute organ toxicity in chemoradiotherapy for head and neck cancer. Oncotarget 7, 65902–65915 (2016).
Johnson, D. B., Nebhan, C. A., Moslehi, J. J. & Balko, J. M. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat. Rev. Clin. Oncol. 19, 254–267 (2022).
Moslehi, J., Lichtman, A. H., Sharpe, A. H., Galluzzi, L. & Kitsis, R. N. Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms. J. Clin. Invest. 131, e145186 (2021).
Axelrod, M. L. et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature 611, 818–826 (2022).
Ban, Y. et al. Radiation-activated secretory proteins of Scgb1a1+ club cells increase the efficacy of immune checkpoint blockade in lung cancer. Nat. Cancer 2, 919–931 (2021).
Yamazaki, T. et al. Boosting CAR T cell expansion and therapeutic activity with low-dose radiation therapy. Int. J. Radiat. Oncol. 108, S158–S159 (2020).
Sugita, M. et al. Radiation therapy improves CAR T cell activity in acute lymphoblastic leukemia. Cell Death Dis. 14, 305 (2023).
John-Aryankalayil, M. et al. Fractionated radiation therapy can induce a molecular profile for therapeutic targeting. Radiat. Res. 174, 446–458 (2010).
Aryankalayil, M. J. et al. Defining molecular signature of pro-immunogenic radiotherapy targets in human prostate cancer cells. Radiat. Res. 182, 139–148 (2014).
Eke, I. et al. Long-term expression changes of immune-related genes in prostate cancer after radiotherapy. Cancer Immunol. Immunother. 71, 839–850 (2022).
Eke, I. et al. Exploiting radiation-induced signaling to increase the susceptibility of resistant cancer cells to targeted drugs: AKT and mTOR inhibitors as an example. Mol. Cancer Ther. 17, 355–367 (2018).
Petroni, G. et al. Radiotherapy delivered before CDK4/6 inhibitors mediates superior therapeutic effects in ER+ breast cancer. Clin. Cancer Res. 27, 1855–1863 (2021).
Eke, I. et al. Long-term tumor adaptation after radiotherapy: therapeutic implications for targeting integrins in prostate cancer. Mol. Cancer Res. 16, 1855–1864 (2018).
Benci, J. L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554.e12 (2016).
Weichselbaum, R. R. et al. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc. Natl Acad. Sci. USA 105, 18490–18495 (2008).
John-Aryankalayil, M. et al. NS-398, ibuprofen, and cyclooxygenase-2 RNA interference produce significantly different gene expression profiles in prostate cancer cells. Mol. Cancer Ther. 8, 261–273 (2009).
Cortez, M. A. et al. Role of miRNAs in immune responses and immunotherapy in cancer. Genes Chromosomes Cancer 58, 244–253 (2019).
John-Aryankalayil, M. et al. Fractionated radiation alters oncomir and tumor suppressor miRNAs in human prostate cancer cells. Radiat. Res. 178, 105–117 (2012).
Eke, I. et al. The lncRNAs LINC00261 and LINC00665 are upregulated in long-term prostate cancer adaptation after radiotherapy. Mol. Ther. Nucleic Acids 24, 175–187 (2021).
Aryankalayil, M. J. et al. Radiation-induced long noncoding RNAs in a mouse model after whole-body irradiation. Radiat. Res. 189, 251–263 (2018).
Aryankalayil, M. J. et al. Analysis of lncRNA-miRNA-mRNA expression pattern in heart tissue after total body radiation in a mouse model. J. Transl. Med. 19, 336 (2021).
Palayoor, S. T. et al. Differential expression of stress and immune response pathway transcripts and miRNAs in normal human endothelial cells subjected to fractionated or single-dose radiation. Mol. Cancer Res. 12, 1002–1015 (2014).
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
Petroni, G., Cantley, L. C., Santambrogio, L., Formenti, S. C. & Galluzzi, L. Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer. Nat. Rev. Clin. Oncol. 19, 114–131 (2022).
Lehrer, E. J. et al. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother. Oncol. 130, 104–112 (2019).
Kotecha, R. et al. The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis. Neuro Oncol. 21, 1060–1068 (2019).
Deng, L. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).
Dovedi, S. J. et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin. Cancer Res. 23, 5514–5526 (2017).
Zhang, X. & Niedermann, G. Abscopal effects with hypofractionated schedules extending into the effector phase of the tumor-specific T-cell response. Int. J. Radiat. Oncol. Biol. Phys. 101, 63–73 (2018).
Wei, J. et al. Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses. Sci. Immunol. 6, eabg0117 (2021).
Verma, V. et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance. Nat. Immunol. 20, 1231–1243 (2019).
Petroni, G., Formenti, S. C., Chen-Kiang, S. & Galluzzi, L. Immunomodulation by anticancer cell cycle inhibitors. Nat. Rev. Immunol. 20, 669–679 (2020).
Jiang, G. L. Particle therapy for cancers: a new weapon in radiation therapy. Front. Med. 6, 165–172 (2012).
Ebner, D. K. et al. The immunoregulatory potential of particle radiation in cancer therapy. Front. Immunol. 8, 99 (2017).
Marcus, D. et al. Charged particle and conventional radiotherapy: current implications as partner for immunotherapy. Cancers 13, 1468 (2021).
Gameiro, S. R. et al. Tumor cells surviving exposure to proton or photon radiation share a common immunogenic modulation signature, rendering them more sensitive to T cell-mediated killing. Int. J. Radiat. Oncol. Biol. Phys. 95, 120–130 (2016).
Yoshimoto, Y. et al. Carbon-ion beams induce production of an immune mediator protein, high mobility group box 1, at levels comparable with X-ray irradiation. J. Radiat. Res. 56, 509–514 (2015).
Onishi, M. et al. High linear energy transfer carbon-ion irradiation increases the release of the immune mediator high mobility group Box 1 from human cancer cells. J. Radiat. Res. 59, 541–546 (2018).
Zhou, H. et al. Carbon ion radiotherapy boosts anti-tumour immune responses by inhibiting myeloid-derived suppressor cells in melanoma-bearing mice. Cell Death Discov. 7, 332 (2021).
Jiménez-Cortegana, C., Galassi, C., Klapp, V., Gabrilovich, D. I. & Galluzzi, L. Myeloid-derived suppressor cells and radiotherapy. Cancer Immunol. Res. 10, 545–557 (2022).
Li, M. et al. Targeted alpha-particle radiotherapy and immune checkpoint inhibitors induces cooperative inhibition on tumor growth of malignant melanoma. Cancers 13, 3676 (2021).
Brenneman, R. J. et al. Abscopal effect following proton beam radiotherapy in a patient with inoperable metastatic retroperitoneal sarcoma. Front. Oncol. 9, 922 (2019).
Tanaka, S., Louis, D. N., Curry, W. T., Batchelor, T. T. & Dietrich, J. Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat. Rev. Clin. Oncol. 10, 14–26 (2013).
Hohlbaum, K. et al. Severity classification of repeated isoflurane anesthesia in C57BL/6JRj mice-assessing the degree of distress. PLoS ONE 12, e0179588 (2017).
Buque, A. & Galluzzi, L. Modeling tumor immunology and immunotherapy in mice. Trends Cancer 4, 599–601 (2018).
Zitvogel, L., Pitt, J. M., Daillere, R., Smyth, M. J. & Kroemer, G. Mouse models in oncoimmunology. Nat. Rev. Cancer 16, 759–773 (2016).
Buque, A. et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat. Commun. 11, 3819 (2020).
Kwon, E. D. et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 15, 700–712 (2014).
Golden, E. B. & Formenti, S. C. Radiation therapy and immunotherapy: growing pains. Int. J. Radiat. Oncol. Biol. Phys. 91, 252–254 (2015).
Lhuillier, C., Vanpouille-Box, C., Galluzzi, L., Formenti, S. C. & Demaria, S. Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers. Semin. Cancer Biol. 52, 125–134 (2018).
Vitale, I., Shema, E., Loi, S. & Galluzzi, L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat. Med. 27, 212–224 (2021).
Tivey, A., Church, M., Rothwell, D., Dive, C. & Cook, N. Circulating tumour DNA — looking beyond the blood. Nat. Rev. Clin. Oncol. 19, 600–612 (2022).
Hodi, F. S. et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 19, 1480–1492 (2018).
Theelen, W. et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir. Med. 9, 467–475 (2021).
Kraehenbuehl, L., Weng, C. H., Eghbali, S., Wolchok, J. D. & Merghoub, T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat. Rev. Clin. Oncol. 19, 37–50 (2022).
Siu, L. et al. Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors. J. Immunother. Cancer 8, e001095 (2020).
Griffin, R. J. et al. Understanding high-dose, ultra-high dose rate, and spatially fractionated radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 107, 766–778 (2020).
Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).
Petroni, G., Buqué, A., Coussens, L. M. & Galluzzi, L. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat. Rev. Drug Discov. 21, 440–462 (2022).
Petroni, G., Buque, A., Zitvogel, L., Kroemer, G. & Galluzzi, L. Immunomodulation by targeted anticancer agents. Cancer Cell 39, 310–345 (2021).
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
Schmid, P. et al. Atezolizumab and Nnab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).
Govindan, R. et al. Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J. Clin. Oncol. 35, 3449–3457 (2017).
Galluzzi, L., Kepp, O., Hett, E., Kroemer, G. & Marincola, F. M. Immunogenic cell death in cancer: concept and therapeutic implications. J. Transl. Med. 21, 162 (2023).
Nagata, S. & Tanaka, M. Programmed cell death and the immune system. Nat. Rev. Immunol. 17, 333–340 (2017).
Boada-Romero, E., Martinez, J., Heckmann, B. L. & Green, D. R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 21, 398–414 (2020).
Sharma, P. & Allison, J. P. Dissecting the mechanisms of immune checkpoint therapy. Nat. Rev. Immunol. 20, 75–76 (2020).
Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).
Galluzzi, L. et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J. Immunother. Cancer 8, e000337 (2020).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
The authors acknowledge support from and the discussion framework provided by a U54 ROBIN grant from NIH National Cancer Institute (#CA274291) and the Breast Cancer Research Foundation (BCRF).
L.G. has received research funding from Lytix Biopharma, Onxeo and Promontory; has received honoraria for consulting or advisory roles from AstraZeneca, Boehringer Ingelheim, EduCom, Imvax, Inzen, the Luke Heller TECPR2 Foundation, Noxopharm, OmniSEQ, Onxeo, Promontory, Sotio and The Longevity Labs; and holds stock options in Promontory. S.C.F. has received research funding from Bristol Myers Squibb, Celldex, Eisai, Eli-Lilly, Merck, Regeneron and Varian; and has received honoraria for consulting or advisory roles from Accuray, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Elekta, EMD Serono, Genentech, MedImmune, Merck, Nanobiotix, Regeneron, Roche, Varian and View Ray. The other authors declare no competing interests.
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Galluzzi, L., Aryankalayil, M.J., Coleman, C.N. et al. Emerging evidence for adapting radiotherapy to immunotherapy. Nat Rev Clin Oncol 20, 543–557 (2023). https://doi.org/10.1038/s41571-023-00782-x