Most clinically applied cancer immunotherapies rely on the ability of CD8+cytolytic T cells to directly recognize and kill tumour cells1–3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4–6. The ability of CD4+effector cells to contribute to antitumour immunity independently of CD8+T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7–10. Here, we describe a mechanism whereby a small number of CD4+T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+T cell targeting. The CD4+effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+antigen-presenting cells. We show that T helper type 1 cell-directed CD4+T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+T cells and natural killer cells and advance cancer immunotherapies.