Proteomic landscape of pan-tissue neuroendocrine carcinomas defines subtype-specific functional architectures, biomarkers and therapeutic targets

Background Neuroendocrine carcinomas (NECs) comprise a highly heterogeneous group of lethal malignancies arising from diverse anatomical sites. Objective We aimed to provide a functional blueprint for bridging the translational gap between fundamental discovery and clinical application in NEC. Design Building on our previously established cross-tissue transcriptional framework, we here performed comprehensive proteomic and phosphoproteomic profiling of 267 NECs spanning 26 anatomical sites. Result This integrated analysis recapitulated the five ANHPY transcriptional subtypes driven by master transcription factors (ASCL1, NEUROD1, HNF4A, POU2F3 and YAP1). These subtypes hijacked distinct lineage developmental programmes, which converged with specific RB1 status to dictate their molecular identities. Synergistic profiling of tissue and plasma proteomes, alongside cell secretomes, nominated subtype-specific diagnostic and therapeutic biomarkers. Specifically, we uncovered NAD + dependency as a metabolic vulnerability unique to subtype H, which is primarily distributed across gastroenteropancreatic NEC. Pharmacological inhibition of the NAD + salvage enzyme NAMPT achieved complete tumour regression in vivo by triggering synthetic lethality in the context of an inherent deficiency in NAD + biosynthesis. We also defined four tumour microenvironment (TME) subtypes that capture the extrinsic diversity of NEC. Notably, the ‘inflamed’ TME subtype was associated with superior immunotherapy responses, yielding an inflammatory signature that robustly stratified patients across diverse tissue origins. Conclusions This study delineated conserved molecular identities, multidimensional biomarkers, the immune landscape and subtype H-specific therapeutic strategies, paving the way for precision medicine in NEC.