An immunosuppressive tertiary lymphoid structure is associated with adverse prognosis in gastric-type endocervical adenocarcinoma

Gastric-type adenocarcinoma (GAC) is the predominant subtype of HPV-independent endocervical adenocarcinoma, characterized by aggressive clinical behavior and poor prognosis. However, its tumor immune microenvironment (TIME) remains largely unexplored. We systematically profiled the immune landscape using bulk RNA sequencing and multiplex immunofluorescence staining and comprehensively analyzed the associations between immune features, clinicopathological parameters, and patient outcomes in a multi-institutional cohort of 153 GAC cases. GAC tumors exhibited sparse T cell but abundant macrophage infiltration, predominantly with M2-polarized macrophages in advanced stage. Tumors with tertiary lymphoid structure (TLS) demonstrated an immunosuppressive milieu characterized by enrichment of B cells, PD1-CD8+ T cells, and regulatory T cells. While TLS-positive patients were associated with poorer prognosis, two patients showed improved survival with chemoradiotherapy. Moreover, the TLS and FIGO stage-based prognostic model was robust in the risk stratification for tumor recurrence. We reveal a distinct immunosuppressive TIME and TLS in GAC. TLS might confer an adverse prognosis. Our findings provide valuable clues for individualized therapy for this aggressive cancer in future.