Beyond local control: radiotherapy-immunotherapy combinations from in situ vaccination to systemic immune remodeling

Radiotherapy (RT) is evolving from local cytotoxicity to systemic immunomodulation. Acting as an in situ vaccine, RT initiates antitumor immunity via immunogenic cell death and cGAS-STING activation. However, RT concurrently triggers counter-regulatory immunosuppression-upregulating PD-L1/TGF-β, expanding Tregs/MDSCs, and inducing T-cell exhaustion-limiting durable systemic control.

We integrate preclinical mechanisms and key clinical evidence for radioimmunotherapy combinations. We analyze how radiation dose, fractionation, and delivery techniques remodel the tumor immune microenvironment and outline matching therapeutic strategies.

Optimal combination requires balancing local tumor control with systemic immune activation while preserving lymphoid reserves. Consolidation durvalumab following concurrent chemoradiotherapy has been shown to improve survival in patients with unresectable stage III non-small cell lung cancer, and SBRT combined with PD-(L)1 blockade has demonstrated benefits in oligometastatic settings. Conversely, radioimmunotherapy combinations have yielded disappointing outcomes in extensive-stage small cell lung cancer and head and neck cancers. Low-dose RT and novel spatial-fractionation strategies offer emerging solutions to reverse immune exclusion.

Efficacy hinges on converting RT-induced immunoadaptation into productive antitumor immunity. Future progress demands biomarker-driven patient selection (e.g., tumor mutational burden, chromosomal instability) and precise orchestration of multi-modality timing. Transitioning toward "immunologically guided precision radiotherapy" will transform RT from a static local therapy into a dynamic component of systemic cancer care.