biostudies-literatureTatsuguchi TP-CAEATELeading Advanced Projects for Medical InnovationJapan Science and Technology AgencyJapan Society for the Promotion of Science277-289https://www.ebi.ac.uk/biostudies/studies/S-EPMC9020568biostudies-literatureUnknown34(5)Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2BInternational immunologyCancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.PMC902056819H00983JP19gm0010001JP20cm0106362Izumi YSakurai THattori YNakamura MSakamoto MNishimoto KKunimura KOyama MTatsuguchi TKubota NBamba TOhki TUruno TSakata DSugiura YOki EFukui YTahara HSuematsu MfalseCancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B2022-01-01T00:00:00Z2022 Apr2025-04-19T20:08:37.521Z2025-02-19T03:27:42.038ZS-EPMC90205683509406510.1093/intimm/dxac002