Radiotherapy-induced PD-L1 conversion in esophageal squamous cell carcinoma: From multidimensional mechanisms to...

Esophageal squamous cell carcinoma (ESCC) remains a formidable malignancy, with patients harboring programmed death ligand-1 (PD-L1)-negative tumors frequently exhibiting an "immune desert" phenotype and poor response to immune checkpoint blockade (ICB). Radiotherapy (RT), traditionally utilized for localized cytoreduction, acts as an in situ vaccine capable of remodeling the tumor immune microenvironment. A potential contributor to RT-ICB synergy is RT-associated modulation of PD-L1 expression, including possible conversion from a PD-L1-negative to a PD-L1-positive state. This review synthesizes ESCC-specific evidence and cross-tumor mechanistic data regarding cGAS-STING-mediated DNA sensing, eIF2α/ATF4-driven translational stress, epigenetic de-repression, metabolic-stromal signaling, and vesicular PD-L1 dissemination. While RT-induced PD-L1 upregulation serves as an adaptive resistance mechanism that can be therapeutically exploited, significant clinical barriers remain. Notable challenges include radiation-induced lymphopenia and overlapping toxicities, despite high pathological complete response rates in recent neoadjuvant RT-ICB trials. To address the needs of the PD-L1-negative population, we evaluate current clinical evidence and ongoing trial strategies. We emphasize the need to refine, rather than replace, existing radiotherapy paradigms through precision-oriented strategies, including careful optimization of spatiotemporal sequencing, cautious exploration of immunomodulatory low-dose radiotherapy, and structural preservation approaches such as tumor-draining lymph node sparing. By modulating stromal and metabolic resistance through refined RT parameters, localized radiation may be effectively translated into durable, systemic antitumor immunity.