An Immune-privileged niche mediates immunotherapy resistance in esophageal carcinoma

Neoadjuvant immunotherapy has reshaped the treatment paradigm for esophageal squamous cell carcinoma (ESCC), yet mechanisms of resistance in non-responders remain poorly understood. Specifically, the spatial orchestration of the tumor microenvironment that limits effective antitumor immunity is not fully elucidated.

Integrating spatial transcriptomic analysis with large-scale tissue pathology, we mapped the spatial architecture of the immune landscape in immunotherapy-resistant ESCC to identify cellular and molecular determinants of treatment failure.

We revealed a distinct immune exclusion phenotype in non-responders, characterized by peritumoral CD8⁺ T cell enrichment coupled with intratumoral depletion. At the invasive front, we identified COL11A1⁺ cancer-associated fibroblasts (CAFs) and SPP1⁺ tumor-associated macrophages as spatially correlated markers of immune exclusion, demarcating regions characterized by limited T cell infiltration. Mechanistically, a distinct subpopulation of LAMC2⁺ tumor cells localized at the tumor boundary acts as the master orchestrator of this barrier. These LAMC2⁺ cells exhibit aberrant lactate metabolism and elevated stemness, driving CAF activation via Semaphorin 3C secretion. Strikingly, this 'LAMC2⁺ boundary tumor cell-immune-privileged niche' axis exhibits pan-cancer correlations with immunotherapy resistance, positioning LAMC2 as a robust predictive biomarker.

In this study, we identify the tumor invasive margin as a critical determinant of immunotherapy resistance in ESCC. By defining the specific spatial markers and molecular architecture of an immune-privileged niche associated with the immune-exclusion barrier, our findings demonstrate the value of spatially resolved microenvironmental analysis. Moreover, we propose that therapeutic targeting of this boundary niche represents a promising strategy to overcome resistance in ESCC.