Integrative molecular-radiopathomic characterization of AIRE-driven immune subtypes in bladder cancer

The efficacy of immunotherapy in bladder cancer (BCa) is highly influenced by tumor heterogeneity, underscoring the urgent need for mechanistic insights and precise molecular subtyping. Adenosine-to-inosine RNA editing (AIRE), a critical post-transcriptional mechanism driving protein diversity, offers a promising lens for decoding the immune microenvironment in BCa. In this study, we established an integrative framework combining molecular, imaging, and pathological data to identify and validate a novel immune-related BCa subtype. Based on multi-center transcriptomic datasets, we employed NMF, WGCNA, and Lasso algorithms to classify tumors into two distinct immune subtypes characterized by different levels of immune cell infiltration and divergent responses to immunotherapy. Mechanistic validation revealed that ANXA1 and RASAL2 may contribute to immunosuppressive niche formation via the TNF-NFκB-CXCL8 axis, potentially acting as molecular triggers for subtype differentiation. Furthermore, radiomic and histopathological analyses at the imaging and tissue levels supported the molecular findings, providing orthogonal validation of subtype-specific characteristics. Collectively, this study introduces an AIRE-based immune molecular subtype of BCa and systematically characterizes it across multiple dimensions. By achieving a closed-loop from identification to validation and clinical translation, our findings offer a new perspective for patients most likely to benefit from immunotherapy and advancing precision treatment strategies in bladder cancer.