A SENP7-SIRT1-IL-10 Axis Driven by DeSUMOylation Promotes Breg Differentiation and Immune Evasion in Colorectal Cancer.

Colorectal cancer (CRC) poses a significant global health challenge, yet immune checkpoint blockade (ICB) therapy benefits only a small subset of patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumours. Through analyses of public single-cell and spatial transcriptomic datasets, primary mouse cell sorting and adoptive transfer experiments, flow cytometry, multiplex immunofluorescence, immunohistochemistry, and coimmunoprecipitation, we revealed that sentrin-specific protease 7 (SENP7) promotes regulatory B-cell (Breg) differentiation and inhibits senescence by activating the expression of the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) via deSUMOylation, thereby enhancing the expression of genes such as interleukin-10 (IL-10). Notably, targeting SENP7 in B cells improved the antitumour efficacy of anti-PD-1 therapy. These findings suggest that inhibiting SENP7 may offer a promising strategy to sensitize immunologically "cold" tumours to immune checkpoint blockade.