Nobiletin in the modified Yiqi Jianpi Decoction enhances the antitumor activity of CD8+ T cells in colorectal cancer by regulating the TIMP1/CD274 axis.

Yiqi Jianpi Decoction (YJD) is a traditional Chinese medicinal formula with reported anticancer properties; however, its effects and regulatory mechanisms in colorectal cancer (CRC) are unclear. Active components and their targets in YJD were identified via the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform, and differentially expressed genes in CRC were extracted from The Cancer Genome Atlas to define the drug-target genes. Potential mechanisms of YJD in CRC were explored through protein-protein interaction network and GO/KEGG enrichment analyses. An in vitro cell model was established: Transwell invasion, wound-healing, and flow-cytometry assays were used to monitor CRC cell viability, while carboxifluorescein diacetate succinimidyl ester assay and lactate dehydrogenase release assay assessed CD8+ T-cell activation. TCMSP screening results showed that the compound Nobiletin (NOB) in YJD interacted with the CRC-related gene TIMP1. In vitro experiments demonstrated that TIMP1 expression levels were positively correlated with CD274 and dampened the cytotoxic effect of CD8+ T cells against CRC. NOB, by binding to TIMP1, inhibited CD274 expression, enhanced CD8+ T-cell activity and proliferation, and thereby boosted their cytotoxic effects on CRC cells. The compound NOB in YJD can enhance the cytotoxicity of CD8+ T cells against CRC by targeting the TIMP1/CD274 axis.