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  • Review Article
  • Published:

Emerging evidence for adapting radiotherapy to immunotherapy

Nature Reviews Clinical Oncology volume 20, pages 543–557 (2023)Cite this article

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Abstract

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.

Key points

  • 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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Fig. 1: Immunostimulatory effects of radiotherapy.
Fig. 2: Immunosuppressive effects of radiotherapy dependent on dose, fractionation and field.
Fig. 3: Strategies to adapt radiotherapy to immunotherapy.

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA

    Lorenzo Galluzzi & Silvia C. Formenti

  2. Sandra and Edward Meyer Cancer Center, New York, NY, USA

    Lorenzo Galluzzi & Silvia C. Formenti

  3. Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA

    Lorenzo Galluzzi

  4. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Molykutty J. Aryankalayil & C. Norman Coleman

  5. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Silvia C. Formenti

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L.G. and S.C.F. conceived the article. L.G. wrote the first version of the manuscript and designed the display items with constructive input from all authors. All authors reviewed and/or edited the manuscript prior to submission.

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Correspondence to Silvia C. Formenti.

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Competing interests

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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Nature Reviews Clinical Oncology thanks J. Schoenfeld, who co-reviewed with A. Wisdom; R. Weichselbaum; J. Welsh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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

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