Radiotherapy for overcoming immune checkpoint inhibitor resistance in esophageal squamous cell carcinoma

Abstract

Immunotherapy has improved outcomes for patients with esophageal squamous cell carcinoma (ESCC), yet a substantial proportion develop resistance. The tumor microenvironment (TME) drives this resistance through four hallmarks: physical barriers formed by cancer-associated fibroblast (CAF)-deposited extracellular matrix (ECM) and elevated interstitial fluid pressure (IFP), enrichment of immunosuppressive cells, effector T cell exhaustion, and impaired antigen presentation. Radiotherapy, a cornerstone of ESCC treatment, has the potential to simultaneously target these barriers through multiple complementary mechanisms. Preclinical evidence suggests that high-dose or ablative radiotherapy can drive CAFs into irreversible senescence, triggering a senescence-associated secretory phenotype (SASP) that upregulates matrix metalloproteinases (MMPs) and degrades ECM. In preclinical models, IFP can be reduced through vascular normalization (low-dose) or tumor debulking (high-dose). There is also evidence, largely from experimental systems, that radiotherapy may eliminate immunosuppressive cells, ameliorate T cell exhaustion, and upregulate MHC class I and PD-L1 expression to restore immune recognition. These immunomodulatory effects appear to be dose- and fractionation-dependent; conventional fractionation often falls below the threshold required to dismantle the physical barrier—a factor that is hypothesized to contribute to, but does not fully account for, the limited success of chemo-immuno-radiotherapy trials to date. Building on this mechanistic framework, we evaluate clinical evidence for radiotherapy-immunotherapy combinations in ICI-resistant ESCC, compare the distinct roles of stereotactic body radiotherapy (SBRT) and low-dose radiotherapy (LDRT), and propose a “barrier-exhaustion score” as a hypothetical tool to guide individualized treatment. This review provides a mechanistic rationale and clinical perspective for radiotherapy-based strategies to overcome immunotherapy resistance in ESCC.