Mechanism of ASIC4 in regulating MHC-I-mediated immune evasion in pancreatic cancer

Immune evasion is a major cause of the poor efficacy of therapies for pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which MHC-I downregulation leads to low infiltration of cytotoxic T lymphocytes in PDAC remains incompletely elucidated. This study aims to identify the molecules responsible for the low expression of MHC-I and potential novel therapeutic targets, thereby providing a theoretical foundation for reversing immune evasion in pancreatic cancer. Bioinformatic analysis identified the acid-sensing ion channel (ASIC4) as a key factor associated with low cytotoxic T lymphocyte (CTL) infiltration in pancreatic ductal adenocarcinoma (PDAC). The correlation between ASIC4 expression and patient prognosis was analyzed via immunohistochemistry (IHC). To elucidate the molecular mechanism by which ASIC4 mediates immune evasion in PDAC, we comprehensively utilized Western blotting, co-immunoprecipitation, and immunofluorescence. An orthotopic PDAC mouse model was established to assess the impact of ASIC4 deletion on CD8⁺ T cell infiltration and tumor growth in vivo. The study found that in pancreatic ductal adenocarcinoma (PDAC), the expression of ASIC4 was significantly upregulated and negatively correlated with the low expression of Major Histocompatibility Complex class I (MHC-I), which was associated with poor patient prognosis. Notably, knocking down ASIC4 led to a significant increase in CD8+ T cell infiltration and slowed tumor growth in vivo. Mechanistic investigations revealed that ASIC4 knockdown restored total and surface levels of MHC-I by inhibiting its autophagic-lysosomal degradation. This study revealed that ASIC4 is highly expressed in PDAC, and its elevated expression is significantly associated with poor prognosis in pancreatic cancer patients. Further mechanistic investigations demonstrated that ASIC4 promotes the degradation of MHC-I via the lysosomal pathway. The subsequent reduction in MHC-I expression leads to decreased infiltration of cytotoxic T lymphocytes (CTLs), ultimately accelerating pancreatic cancer progression. Silencing ASIC1 restored MHC-I expression and enhanced the antitumor efficacy of CD8⁺ T cells. These findings identify ASIC4 as a potential therapeutic target and provide a theoretical foundation for reversing the immune-cold phenotype of PDAC and developing combined immunotherapy strategies.