Abstract Background: Gastric cancer (GC) is a leading cause of cancer-related death, with poor 5-year survival rates for advanced stages, emphasizing the need for biomarkers to guide immunotherapy. Tertiary lymphoid structures (TLSs) in the tumor microenvironment have been linked to favorable prognosis and immune checkpoint blockade response, but the specificity of GC-derived TLS transcriptional signatures and their utility across tumor types remain unclear. We used single-cell-resolution spatial transcriptomics to construct a GC-derived TLS score and evaluated its prognostic and immunotherapy-predictive value in GC and pan-cancer cohorts. Methods: In a cohort of 100 GC patients, TLS presence and maturation were assessed on surgical specimens by H in melanoma immunotherapy cohorts, high-score patients consistently had superior overall survival. In the humanized GC PDOX model, high TLS score tumors showed enhanced response to anti-PD-1/CTLA-4, with increased tumor cell apoptosis and higher T- and B-cell infiltration, potentially enhancing anti-tumor immunity. Conclusions: We developed the first GC-derived TLS score using single-cell-resolution spatial transcriptomic data and validated its performance across multiple tumor types and in a humanized GC model. This high-resolution score was consistently associated with improved response and survival after immune checkpoint blockade, supporting its use as a precise biomarker for patient stratification and immunotherapy guidance across cancers. Citation Format: Wenbo Zhu, Hongru Shen, Huijun Wang, Ben Liu, Xiangchun Li, Kexin Chen. Gastric cancer-derived tertiary lymphoid structure score from single-cell spatial transcriptomics with pan-cancer validation for immunotherapy response abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2436.
Zhu et al. (Fri,) studied this question.