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

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.