Abstract / Summary
ABSTRACT Background Colorectal cancer liver metastasis (CRLM) is the leading cause of mortality in colorectal cancer (CRC) patients, for which effective treatments remain limited. The mechanisms by which tumor cells evade immune surveillance and escape cytotoxic killing remain poorly understood. SERPINB9 (SB9) has been implicated in immune evasion in several malignancies. This study aimed to investigate the functional significance of SB9 in CRLM progression and immune checkpoint blockade (ICB) resistance. Methods SB9 expression was evaluated in clinical CRLM specimens by immunohistochemistry and in public transcriptomic databases. Functional consequences of stable Sb9 knockdown were assessed using syngeneic intrasplenic injection mouse models with CT26 and MC38 cell lines. Tumor‐infiltrating lymphocytes were profiled by flow cytometry, molecular mechanisms explored via bulk and single cell RNA sequencing, and the therapeutic impact of Sb9 knockdown combined with anti‐PD‐1 treatment evaluated in vivo. Results SB9 was highly expressed in CRLM specimens, and elevated SB9 levels were associated with poor prognosis and immunotherapy resistance. Sb9 knockdown substantially suppressed liver metastasis and restored anti‐PD‐1 sensitivity in immunocompetent mice. Mechanistically, Sb9 depletion was associated with upregulated MHC‐I surface expression on tumor cells and enhanced CD8 + T cell antitumor activity in the hepatic metastatic microenvironment; CD8 + T cell depletion abrogated these effects, confirming immune dependence. Conclusions SB9 promotes CRLM and contributes to ICB resistance through mechanisms associated with impaired MHC‐I‐mediated antigen presentation and attenuated CD8 + T cell anti‐tumor immunity. These findings support SB9 as a potential therapeutic target for modulating immunotherapy resistance in CRLM.