Shaoyao Decoction Inhibits Colorectal Cancer Progression by Targeting PD-L1 to Reprogram the Immunosuppressive Tumor Microenvironment.

Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype accounting for ~ 85% of cases, remains refractory to immune checkpoint inhibitors due to persistent immunosuppression. Shaoyao Decoction (SYD), a traditional Chinese herbal formula, is known for its anti-inflammatory and anticancer effects. However, the mechanisms by which it modulates immune responses in colorectal cancer (CRC) remain poorly understood. Here, we evaluated SYD's efficacy in AOM/DSS-induced colitis-associated CRC and PD-L1-overexpressing MC38 syngeneic models, using the PD-1/PD-L1 inhibitor BMS-202 as a positive control. In vivo, SYD significantly suppressed tumor growth, normalized colon structure, and reduced tumor burden, with efficacy comparable to BMS-202 but without overt toxicity. Mechanistically, SYD downregulated PD-L1 expression in tumor and spleen tissues, shifted serum cytokines toward a pro-inflammatory profile characterized by increased IL-2 and IFN-γ as well as decreased IL-10 and TGF-β, and restored CD4⁺/CD8⁺ T cell balance. In vitro, SYD inhibited the viability of PD-L1-overexpressing MC38 cells and reduced PD-L1 mRNA expression. Collectively, SYD exerts potent anti-CRC effects by targeting PD-L1 to remodel the immunosuppressive tumor microenvironment. As a multi-target agent, it holds great promise for MSS-CRC, bridging TCM with modern immuno-oncology.