Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1^KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.

改善T细胞衰竭和增强效应子功能是改善免疫疗法的有希望的策略。在这里，我们显示HPK1-NFκB-Blimp1轴介导T细胞功能障碍。MAP4K1的高表达（编码HPK1）与T细胞衰竭增加和几种癌症类型的患者存活率降低有关。在MAP4K1 ^KO中在小鼠中，肿瘤的生长比野生型小鼠慢，并且浸润性T细胞的疲惫程度降低，活性和增殖性更高。我们进一步显示，遗传耗竭，药理学抑制或蛋白水解靶向嵌合体（PROTAC）介导的HPK1降解在血液和实体瘤的各种临床前小鼠模型中提高了基于CAR-T细胞的免疫疗法的功效。这些策略比在CAR-T细胞中遗传消除PD-1更有效。因此，我们证明HPK1是T细胞功能障碍的介体，并且是改善免疫治疗反应的有吸引力的可药物化靶标。