Tumor CMTM6 is known to regulate programmed death-ligand 1 expression and affect the cytotoxicity of infiltrating T cells, while its impact on natural killer (NK) cells and tumor malignancy remains to be fully understood. This study aimed to investigate the influences of tumor CMTM6 on NK cell infiltration and tumor progression.

We established animal models of gastric cancer to assess the effects of CMTM6 knockdown on the NK cell infiltration into the tumor. Tumor tissue microarray was used to evaluate the correlation between CMTM6 expression and tumor differentiation. Proteomic analysis was performed to identify potential downstream effectors of CMTM6, validated by coimmunoprecipitation. The lysosomal and proteasomal degradation of the effector was determined by cycloheximide chase given CMTM6 knockdown or over-expression in vitro.

CMTM6 knockdown significantly enhanced the infiltration of NK cells into gastric tumors and suppressed tumor growth. CMTM6 protein level decreased in poorly differentiated gastric cancer, correlating with the loss of epithelial integrity. We identified poliovirus receptor-related 2 (PVRL2/Nectin-2) as a potential effector of CMTM6, which functions as an adhesion molecule critical for cellular junctions and the epithelial barrier. CMTM6 interacts with Nectin-2 via RAB14/RAB11 mediated trafficking, and CMTM6 inhibits Nectin-2 degradation through both lysosomal and proteasomal pathways.

Inhibition of CMTM6 expression enhances host anti-tumor immunity by increasing NK cell infiltration while potentially influencing the tumor progression.