In sum, our studies provide ‘proof-of-concept’ for the therapeutic targeting of GPR15-GPR15L axis in CRC treatment; intratumoral administration of GPR15L attenuates tumor growth in a GPR15-dependent manner by shaping an anti-tumor immune environment enriched in cytolytic T, NK and NKT cells. The gene discussed is GPR15LG; the disease is colorectal carcinoma.