INHBB Promotes Colorectal Cancer Progression by Inducing CD8+ T Cell Exhaustion via the ACVR2B-SMAD Signaling Axis.

To investigate the expression pattern, biological functions and regulatory mechanisms of inhibin beta B (INHBB) in colorectal cancer (CRC), and to clarify its role in mediating CD8+ T cell exhaustion via the INHBB-ACVR2B-SMAD signaling axis for identifying a novel therapeutic target in CRC targeted immunotherapy, we analyzed the expression profile and prognostic value of INHBB in CRC tissues using The Cancer Genome Atlas database. Stable INHBB knockdown and overexpression CRC cell lines were constructed, and the malignant phenotypes were evaluated by Transwell assays, flow cytometry and other functional experiments. The interaction between INHBB and ACVR2B was verified by co-immunoprecipitation and immunofluorescence, and the in vivo regulatory effects of this pathway were determined using mouse xenograft tumor models combined with SMAD inhibitors. INHBB was upregulated in CRC tissues and associated with poor prognosis. Functional assays demonstrated that INHBB promoted the proliferation and invasion and suppressed the apoptosis of CRC cells. Mechanistically, INHBB bound to ACVR2B on CD8+ T cells, activated SMAD signaling, and triggered CD8+ T cell exhaustion, whereas blockade of the SMAD pathway reversed INHBB-mediated immunosuppression and tumor progression. Collectively, INHBB dually regulates the malignant phenotypes of CRC cells and CD8+ T cell function through the INHBB-ACVR2B-SMAD axis, and targeting this axis may represent a promising therapeutic strategy for CRC immunotherapy.