In summary, we described the mechanism by which VPS9D1-AS1 promoted tumor immune evasion through the TGF-β signaling pathways and ISGs and provided compelling evidence that the VPS9D1-AS1/TGF-β/ISG axis might serve as a drug target to enhance the efficacy of ICB treatment against CRC. The gene discussed is VPS9D1; the disease is colorectal carcinoma.