Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8⁺ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8⁺ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8⁺ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8⁺ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (T_TSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-T_TSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-T_TSM cells could be harnessed to potentiate anti-tumor immunotherapy.

阻断 PD-1/PD-L1 信号转导改变了癌症治疗，并被认为可以在肿瘤微环境 (TME) 中释放耗尽的肿瘤反应性 CD8 ^{+ T 细胞。}然而，最近的研究也表明，全身性肿瘤反应性 CD8 ⁺ T 细胞可能对 PD-1/PD-L1 免疫疗法有反应。这些差异突出了进一步定义对 PD-1/PD-L1 阻断的肿瘤特异性 CD8 ⁺ T 细胞应答者的重要性。在这里，使用多个临床前肿瘤模型，我们发现肿瘤引流淋巴结 (TdLN) 中的肿瘤特异性 CD8 ^{+细胞子集并未功能耗尽，但表现出典型的记忆特征。}TdLN 衍生的肿瘤特异性记忆 (T _TSM) 细胞在肿瘤发生早期建立了记忆相关的表观遗传程序。更重要的是，TdLN-T _TSM细胞在过继转移后表现出优异的抗肿瘤治疗效果，并且被描述为对 PD-1/PD-L1 阻断的真正反应者。这些发现强调 TdLN-T _TSM细胞可用于增强抗肿瘤免疫疗法。