<p>The involvement of tumour-resident memory T (T_RM) cells in responses to immune checkpoint inhibitors remains unclear. Here, we show that while CD103⁺CD8 T_RM cells are involved in response to PD-1 blockade, CD49a⁺CD4 T_RM cells are required for the response to anti-CTLA-4. Using preclinical mouse models, we demonstrate that the benefits of anti-PD-1 treatment are compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. By contrast, the benefits of anti-CTLA-4 are decreased by anti-CD4 and anti-CD49a neutralizing antibodies. Single-cell RNA sequencing on tumour-infiltrating T-lymphocytes (TIL) reveals a CD49a⁺CD4 T_RM signature, enriched in <i>Ctla-4</i> transcripts, exacerbated upon anti-CTLA-4. CTLA-4 blockade expands CD49a⁺CD4 T_RM cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49a⁺CD4 T_RM signature enriched in <i>CTLA-4</i> and cytotoxicity-linked transcripts is also identified in human TILs. Multiplex immunohistochemistry in a cohort of anti-CTLA-4-plus-anti-PD-1-treated melanomas reveals an increase in CD49a⁺CD4 T-cell density in pre-treatment tumours, which correlates with higher rates of patient progression-free survival. Thus, CD49a⁺CD4 T_RM cells may correspond to a predictive biomarker of response to combined immunotherapy.</p>