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Strategies to disrupt Treg-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for this failure are poorly understood. By modeling Treg-targeted immunotherapy in mice, we find that a subset of CD4+ Foxp3- conventional T (Tconv) cells with potent suppressive function undergoes activation and expansion upon depletion of Foxp3+ Treg cells and limits therapeutic efficacy. We noted that Foxp3- Tconv cells within tumors adopt a Treg-like transcriptional profile upon Treg depletion and acquire suppressive function. This is attributable to a Th2-like subset of CD4+ Tconv cells marked by expression of (C-C motif) receptor 8 (CCR8) and enriched in Treg-associated transcripts. CCR8+ Tconv cells are found in mouse and human tumors. Upon Treg depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, resulting in IL-10 dependent suppression of anti-tumor immunity. Consequently, conditional deletion of Il10 within T cells augments anti-tumor efficacy upon Treg-depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg-targeted therapies. Overall design: Syngeneic B16-F10 melanoma cells were subcutaneously implanted into Foxp3EGFP-DTR mice and ablated Treg cells through administration of DTx. T cells were isolated by FACS and subjected to scRNA-Seq analysisxref:PubMed:38100544ENAfalseAcquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion [scRNA-seq]Acquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion [scRNA-seq]2025-09-242024-01-15PRJNA992495GSE2368241009038100544