Robust CD8⁺ T cell memory is essential for long-term protective immunity but is often compromised in cancer, where T cell exhaustion leads to loss of memory precursors. Immunotherapy via checkpoint blockade may not effectively reverse this defect, potentially underlying disease relapse. Here we report that mice with a CD8⁺ T cell–restricted neuropilin-1 (NRP1) deletion exhibited substantially enhanced protection from tumor rechallenge and sensitivity to anti-PD1 immunotherapy, despite unchanged primary tumor growth. Mechanistically, NRP1 cell-intrinsically limited the self-renewal of the CD44⁺PD1⁺TCF1⁺TIM3⁻ progenitor exhausted T cells, which was associated with their reduced ability to induce c-Jun/AP-1 expression on T cell receptor restimulation, a mechanism that may contribute to terminal T cell exhaustion at the cost of memory differentiation in wild-type tumor-bearing hosts. These data indicate that blockade of NRP1, a unique ‘immune memory checkpoint’, may promote the development of long-lived tumor-specific T_mem that are essential for durable antitumor immunity.

强大的 CD8 ⁺ T 细胞记忆对于长期保护性免疫至关重要，但在癌症中经常受到损害，其中 T 细胞衰竭会导致记忆前体的丧失。通过检查点阻断的免疫疗法可能无法有效逆转这一缺陷，可能是潜在的疾病复发。在这里，我们报告了具有 CD8 ⁺ T 细胞限制性神经纤毛蛋白-1 (NRP1) 缺失的小鼠表现出显着增强的对肿瘤再攻击的保护和对抗 PD1 免疫疗法的敏感性，尽管原发性肿瘤生长没有变化。^{从机制上讲，NRP1 细胞本质上限制了 CD44 +} PD1 ⁺ TCF1 ⁺ TIM3的自我更新^-祖细胞耗尽 T 细胞，这与它们在 T 细胞受体再刺激时诱导 c-Jun/AP-1 表达的能力降低有关，这种机制可能以野生型肿瘤中的记忆分化为代价导致终末 T 细胞衰竭 -承载主机。这些数据表明，阻断 NRP1（一种独特的“免疫记忆检查点”）可能会促进长寿命的肿瘤特异性 T _mem的发展，这对于持久的抗肿瘤免疫至关重要。