Radiotherapy and immunotherapy in cancer treatment: mechanisms of clinical synergy
Lu Lu, Liufu Deng
Lu Lu, Liufu Deng
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Radiotherapy and immunotherapy in cancer treatment: mechanisms of clinical synergy

Abstract

Synergizing radiotherapy (RT) with immune checkpoint inhibitors has emerged as a promising strategy for solid tumors. RT acts as a potent immunomodulator, capable of functioning as an in situ vaccine through the induction of immunogenic cell death and activation of innate immune sensing, thereby promoting DC maturation and CD8+ T cell responses. However, RT also triggers counter-regulatory immunosuppression, including PD-L1 upregulation and the recruitment of suppressive cells, providing the biological rationale for synergy. Here, we systematically review advances in radioimmunotherapy, covering immunomodulatory mechanisms, clinical optimization of dose and sequencing, and the emerging role of artificial intelligence (AI) in guiding treatment paradigms. We adopt a spatial interaction–centric perspective to synthesize current knowledge on how RT governs the DC/CD8+ T cell interaction axis across the tumor microenvironment and tumor-draining lymph nodes, aiming to chart a rational course from empirical combination toward personalized, precision radioimmunotherapy. Furthermore, we explore how AI-driven analysis of radiomics and multiomics data is being applied to predict responders and personalize treatment planning.

Authors

Lu Lu, Liufu Deng

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Figure 3

TDLN-orchestrated DC/CD8+ T cell immunity.

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TDLN-orchestrated DC/CD8+ T cell immunity. The DC/CD8+ T cell axis funct...
The DC/CD8+ T cell axis functions across 2 anatomically and functionally distinct compartments. In TDLNs (left), CCR7+ mature DCs from irradiated tumors cross-present tumor antigens on MHC I to naive CD8+ T cells. DCs establish specialized niches to generate and maintain TCF1+ TPEX cells, the principal drivers of durable antitumor responses. Tregs within TDLNs can suppress priming. In the TME (right), T cells enter and further differentiate upon antigen reencounter to exert an antitumor response, including an abscopal effect. Naive CD8+ T cells (TCF1+CD44–) are primed into TPEX in lymph nodes and then migrate to the TME. Within the TME, GZMK+CD8+ T cells represent a distinct effector memory–like population and occupy an intermediate position within intratumoral CD8+ T cell differentiation. Progenitors are the main responders to ICIs, whereas terminally exhausted cells are largely resistant. TEF, effector CD8+ T cells; TEX, terminally exhausted CD8+ T cells.