TMEM184A-mediated autophagy in MHC-I degradation promotes tumor immune evasion.

The dominance of immunotherapy-insensitive MSS colorectal cancers (CRCs), which represent most cases, contrasts sharply with the treatable MSI-H minority, making this disparity a key obstacle to progress. It is urgent to identify genes driving immune evasion in MSS CRCs. Here, using a genome-wide CRISPR screen in a syngeneic tumor model under immune pressure, we identify TMEM184A as a previously unknown tumor-intrinsic regulator of immune evasion. Its genetic deletion in murine models enhanced CD8+ T cell infiltration and increased surface MHC-I expression on cancer cells, as shown by flow cytometry, immunohistochemistry, immunofluorescence and RNA-seq.

Mechanistically, TMEM184A functions as a novel macroautophagy/autophagy receptor by binding GABARAPL2, directly promoting the autophagic degradation of IFNG-induced MHC-I. In murine models, genetic deletion of Tmem184a led to a significant increase in both CD8+ T cell infiltration and surface MHC-I expression on cancer cells. Functional studies in vivo and in vitro confirmed that this impaired antigen presentation causally facilitates immune evasion.

Our findings establish MHC-I autophagic degradation as a critical pathway regulating immune evasion and position TMEM184A as a pivotal molecular hub in this process.

Notably, treatment with the autophagy inhibitor chloroquine significantly increased surface MHC-I levels and enhanced the efficacy of anti-PDCD1/PD-1 therapy specifically in TMEM184A-high tumors. This work suggests that targeting TMEM184A or its associated autophagic pathway could restore antigen presentation in MHC-I-deficient tumors, offering a potential combinatorial strategy to overcome adaptive immune resistance in multiple malignancies. Abbreviations: AKP organoids:apcandtrp53knockout, KRASG12Dmutation organoids; CRC: colorectal cancer; CQ: chloroquine; GABARAPL2/Atg8: GABA type A receptor associated protein like 2; IF: immunofluorescence; IFNG: interferon gamma; IHC: immunohistochemistry; MHC-I: major histocompatibility complex I; qRT-PCR: quantitative reverse transcription PCR; MSI-H: microsatellite instability-high; MSS: microsatellite-stable; TMEM184A: transmembrane proteins 184a.