CTMP-REV7 axis modulates MHC-I antigen presentation via CDK1-AKT crosstalk in MSI-L/MSS colorectal cancer

Microsatellite instability-low/microsatellite stable (MSI-L/MSS) colorectal cancer (CRC) exhibits limited responsiveness to immune checkpoint inhibitors due to low tumor mutational burden and insufficient neoantigen generation. Carboxyl-terminal modulator protein (CTMP) is a potential regulatory molecule that may reshape tumor immunogenicity and metabolic patterns, yet its mechanisms in MSI-L/MSS CRC remain poorly understood.

We systematically investigated CTMP function by integrating clinical sample analysis (GEO database, n = 71 paired tissue microarray, and pretreatment specimens from 11 refractory patients receiving anti-PD-1 plus fruquintinib), in vitro experiments (MSS CRC cells with CTMP knockdown/overexpression, assessed for proliferation, mitochondrial function, lipid metabolism, AKT/PD-L1 signaling, and MHC-I/HLA-B expression), proteomic screening (immunoprecipitation-mass spectrometry to identify CTMP-interacting proteins), structural validation (co-immunoprecipitation, AlphaFold Multimer, GST pulldown with truncation/point mutations), and in vivo studies (immunocompetent BALB/c mice with CT26 syngeneic tumors).

High CTMP expression and low HLA-B expression were significantly associated with shortened overall survival in patients with MSI-L/MSS colon adenocarcinoma, as well as with progressive disease in an anti-PD-1/fruquintinib resistance cohort. Mechanistically, CTMP orchestrated an immunosuppressive tumor microenvironment by sustaining AKT/PD L1 signaling, suppressing HLA B expression, and promoting fatty acid metabolism. Proteomic screening identified a previously unreported high-affinity interaction between CTMP and REV7, which facilitated CDK1 mediated G2/M progression and further repressed HLA B expression. CTMP knockdown or REV7 overexpression diminished CDK1 activity, induced G2/M phase arrest, and restored HLA B expression in a cGAS signaling-relevant manner. Furthermore, disruption of the CTMP-REV7 signaling axis modulated CDK1 and AKT activity under IFN-γ-driven immune stress, affecting MHC-I expression. In immunocompetent murine models, CTMP knockdown or REV7 overexpression suppressed tumor growth, upregulated HLA B expression, and enhanced intratumoral CD8⁺ T cell infiltration. Moreover, REV7 overexpression synergized with IFN-γ to promote the release of chemokines (CXCL9, CXCL10, TNF α), leading to marked tumor regression in CTMP-KD tumors.

We delineate that CTMP drives immune evasion in MSI-L/MSS CRC through a novel CTMP-REV7-CDK1 axis that couples metabolic reprogramming, cell cycle control, and MHC-I antigen presentation, with AKT signaling serving as a critical crosstalk node. These findings implicate this integrated axis as a therapeutic target to restore tumor immunogenicity and overcome immunotherapy resistance in immunologically "cold" MSI-L/MSS colorectal cancer.