Cytotoxic T lymphocytes (CTLs) are central effector cells in antitumor immunotherapy. However, the complexity of immunosuppressive factors in the immune system contributes to the low response rates of current CTL-based immunotherapies. Here, we propose a novel holistic strategy including a priming response, promoting activity, and relieving suppression of CTLs, aiming to strengthen the effect of personalized postoperative autologous nanovaccines. The nanovaccine (C/G-HL-Man) fused the autologous tumor cell membrane with dual adjuvants (CpG and cGAMP), and could effectively accumulate in lymph nodes and promote antigen cross presentation by dendritic cells to prime a sufficient specific-CTL response. The PPAR-α agonist fenofibrate was used to regulate T-cell metabolic reprogramming to promote antigen-specific CTLs activity in the harsh metabolic tumor microenvironment. Finally, the PD-1 antibody was used to relieve the suppression of specific-CTLs in the immunosuppressive tumor microenvironment. In vivo, the C/G-HL-Man exhibited strong antitumor effect in the B16F10 murine tumor prevention model and the B16F10 postoperative recurrence model. In particular, combination therapy with nanovaccines, fenofibrate, and PD-1 antibody effectively inhibited the progression of recurrent melanoma and prolonged the survival time. Our work highlights the critical role of the T-cell metabolic reprogramming and PD-1 blocking in autologous nanovaccines, offering a novel strategy for strengthening the function of CTLs.

细胞毒性 T 淋巴细胞(CTL) 是抗肿瘤免疫疗法中的中枢效应细胞。然而，免疫系统中免疫抑制因子的复杂性导致当前基于 CTL 的免疫疗法的反应率较低。在这里，我们提出了一种新的整体策略，包括启动反应、促进活动和解除对 CTL 的抑制，旨在加强个性化术后自体纳米疫苗的效果。纳米疫苗 (C/G-HL-Man) 将自体肿瘤细胞膜与双佐剂（CpG 和 cGAMP）融合，可有效地在淋巴结中积聚并促进树突状细胞的抗原交叉呈递，从而引发足够的特异性 CTL 反应。PPAR-α激动剂非诺贝特用于调节 T 细胞代谢重编程，以促进严酷代谢肿瘤微环境中的抗原特异性 CTL 活性。最后，PD-1 抗体被用于解除免疫抑制肿瘤微环境中特异性 CTL 的抑制。在体内，C/G-HL-Man 在 B16F10 小鼠肿瘤预防模型和 B16F10 术后复发模型中表现出很强的抗肿瘤作用。特别是纳米疫苗、非诺贝特和PD-1抗体的联合治疗有效抑制了复发性黑色素瘤的进展并延长了生存时间。我们的工作强调了 T 细胞代谢重编程和 PD-1 阻断在自体纳米疫苗中的关键作用，提供了一种加强 CTL 功能的新策略。