Tumoral AMER1 driven dopamine synthesis triggers cancer cell pyroptosis and licenses CD8+ T cell immunity in colorectal cancer.

While classical tumor suppressors in colorectal cancer (CRC) are predominantly recognized for restraining cell-autonomous proliferation, their extrinsic mandate in orchestrating the tumor immunometabolic niche remains poorly defined. Clinically, we document that APC membrane recruitment protein 1 (AMER1) downregulation correlates with advanced progression and cytotoxic CD8+ T cell spatial exclusion in CRC patients. Using parallel homograft models in diverse host immune backgrounds, we show that tumoral AMER1 confers robust in vivo tumor-suppressive effects that are dependent on a fully functional immune system. Single-cell RNA sequencing reveals that tumoral AMER1 enrichment actively preserves CD8+ T cell effector stemness by expanding the CXCR5+ precursor exhausted subset (Tpex) across regional lymph nodes and primary tumor microenvironments. Integrated multi-omics and biochemical tracking identify dopamine (DA) as the conserved neurometabolic effector driving this niche remodeling. Mechanistically, AMER1 physically binds and rescues dopa decarboxylase (DDC) from post-translational degradation to sustain tumoral DA secretion; conversely, AMER1 loss creates a localized DA void. Cell-autonomously, tumoral DA accumulation triggers gasdermin D (GSDMD)-dependent tumor pyroptosis. Therapeutically, local DA administration halts multi-lineage carcinoma progression by reversing CD8+ T cell terminal exhaustion and reinforcing central memory differentiation. Collectively, our findings redefine AMER1 as a critical immunometabolic gatekeeper and establish neurotransmitter metabolic bypassing as a promising therapeutic strategy for CRC.