LAUSR

&NA; Resistance to checkpoint‐blockade treatments is a challenge in the clinic. We found that although treatment with combined anti‐CTLA‐4 and anti‐PD‐1 improved control of established tumors, this combination compromised anti‐tumor immunity in the low tumor burden (LTB) state in pre‐clinical models as well as in melanoma patients. Activated tumor‐specific T cells expressed higher amounts of interferon‐&ggr; (IFN‐&ggr;) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor‐specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower‐frequency clonotypes. Additionally, combination therapy induced higher IFN‐&ggr; production in the LTB state than in the high tumor burden (HTB) state on a per‐cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN‐&ggr; secretion in the LTB state contributes to the development of an immune‐intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies. Graphical Abstract Figure. No caption available. HighlightsCombination checkpoint blockade leads to impaired efficacy with low tumor burdenThis impairment results from IFN‐&ggr;‐mediated deletion of tumor‐reactive T cellsAICD is an immune‐intrinsic mechanism of therapeutic resistance to checkpoint blockade &NA; Although immune checkpoint blockades are being combined to enhance anti‐tumor efficacy, Pai et al. find that this approach can lead to therapy resistance in the low tumor burden setting. Potent immunotherapy in this setting overdrives tumor‐reactive T cells, leading to their death. Optimal immunotherapy could therefore be disease‐context dependent.