Spatially fractionated radiotherapy and immunotherapy: a synergistic strategy for systemic anti-tumor immunity

This review summarizes preclinical evidence on the immunomodulatory mechanisms of spatially fractionated radiotherapy (SFRT) alone and in combination with immune checkpoint inhibitors (ICIs), as well as clinical evidence for SFRT with or without immunotherapy.

Conventional radiotherapy (CRT) has a dual impact on anti-tumor immunity, simultaneously activating immune responses and inducing immunosuppression. Preclinical studies show that SFRT can remodel the tumor microenvironment (TME) and tumor vasculature, enhance effector immune cell infiltration, regulate cytokine networks, and elicit both bystander and abscopal effects. However, the magnitude and direction of these effects vary substantially across SFRT modalities, parameters, and tumor types.When combined with ICIs, SFRT shows promising tumor-control activity in preclinical models, yet it does not consistently outperform CRT plus ICI. Clinical evidence is still limited to small palliative cohorts and case reports without systematic immune monitoring. Nonetheless, isolated cases have reported abscopal responses and reversal of ICI resistance, highlighting the need for prospective, biomarker‑driven studies to define the immunologic and clinical role of SFRT.

Preclinical evidence suggests that SFRT can induce both bystander and abscopal effects. These effects may help overcome immune resistance when SFRT is combined with immunotherapy, ultimately improving the therapeutic ratio of radiation and enhancing the efficacy of ICIs. However, current clinical data are still preliminary, and further systematic research is needed to optimize SFRT parameters, treatment sequencing, and tumor-specific responses.