CLCA1 as an immune prognostic biomarker and therapeutic target in colorectal cancer.

BACKGROUND

Colorectal cancer (CRC) progression is profoundly shaped by the tumor immune microenvironment. Increasing evidence suggests that dysregulated immune activation and immune evasion jointly contribute to tumor progression and therapeutic resistance. This study aims to identify novel immune-related biomarkers and explore combinatorial therapeutic strategies for overcoming immunosuppression in CRC by investigating the interplay between chloride channel accessory 1 (CLCA1)-mediated immune activation and serine proteinase inhibitor B9 (SERPINB9)-driven immune escape.

METHODS

Integrated multi-omics analyses were performed to identify key immune-related prognostic biomarkers in CRC and to construct a prognostic immune signature. The predictive performance of the model was validated in independent cohorts. Functional assays were conducted in female C57BL/6J mice to evaluate the effects of CLCA1 on tumor growth and immune cell infiltration. Mechanistic analyses were used to investigate the regulatory relationship between CLCA1 and SERPINB9. In addition, computational drug screening, together with structural and biophysical assays, was applied to identify candidate small molecules targeting CLCA1.

RESULTS

CLCA1 was identified as a central immune-related prognostic biomarker in CRC. A 14-gene immune signature effectively stratified patients into distinct risk groups and showed robust predictive value across independent cohorts. Functional studies demonstrated that CLCA1 overexpression suppressed tumor growth and promoted the infiltration of cytotoxic immune cells. Mechanistically, CLCA1 downregulated SERPINB9, a granzyme B (GZMB) inhibitor that plays a pivotal role in immune evasion. Notably, combined CLCA1/SERPINB9 expression status provided improved prognostic stratification compared with either marker alone. Computational screening further identified phloretin as a potential CLCA1-targeting compound, which was supported by structural and biophysical validation.

CONCLUSIONS

These findings identify CLCA1 as a prognostic immune modulator and a potential therapeutic target in CRC. The functional interaction between CLCA1 and SERPINB9 highlights a mechanistic axis linking immune activation and immune escape. Moreover, phloretin emerges as a candidate small molecule for modulating CLCA1, although its in vivo immunomodulatory effects and target dependency require further validation.