biostudies-literatureBae HRNational Research Foundation of Korea297https://www.ebi.ac.uk/biostudies/studies/S-EPMC12411337biostudies-literatureUnknown74(9)Although checkpoint immunotherapy has primarily focused on CD8⁺ T cells, emerging evidence highlights an important role for cytotoxic CD4⁺ T cells in mediating therapeutic responses. However, research on the functional properties of cytotoxic CD4⁺ T cells in the context of immunotherapy is still at an early stage and remains insufficiently defined. Utilizing single-cell RNA-sequencing datasets obtained from metastatic melanoma patients treated with checkpoint inhibitors targeting PD-1 and/or CTLA-4, we performed transcriptomic profiling of conventional CD4⁺ T cells, excluding proliferative and regulatory (FOXP3⁺) subsets, and compared responders and non-responders as distinct groups. Importantly, our analysis identified distinct clusters that discriminate between responders and non-respondCancer immunology, immunotherapy : CIICytotoxic CD4⁺ T cells exhibit an immunosuppressive shift in checkpoint immunotherapy resistance in melanoma patients.PMC12411337RS-2024-00342528RS-2023-00213596Kim SBae HRSon BYoung HAKwon EYHwang KfalseCytotoxic CD4⁺ T cells exhibit an immunosuppressive shift in checkpoint immunotherapy resistance in melanoma patients.Although checkpoint immunotherapy has primarily focused on CD8⁺ T cells, emerging evidence highlights an important role for cytotoxic CD4⁺ T cells in mediating therapeutic responses. However, research on the functional properties of cytotoxic CD4⁺ T cells in the context of immunotherapy is still at an early stage and remains insufficiently defined. Utilizing single-cell RNA-sequencing datasets obtained from metastatic melanoma patients treated with checkpoint inhibitors targeting PD-1 and/or CTLA-4, we performed transcriptomic profiling of conventional CD4⁺ T cells, excluding proliferative and regulatory (FOXP3⁺) subsets, and compared responders and non-responders as distinct groups. Importantly, our analysis identified distinct clusters that discriminate between responders and non-respond2025-01-01T00:00:00Z2025 Sep2026-05-29T19:43:38.688Z2026-04-08T05:50:29.448ZS-EPMC124113374090621110.1007/s00262-025-04145-6