Combining immune checkpoint blockade with chemotherapy through nanotechnology is promising in terms of safety and efficacy. However, the distinct subcellular distribution of each ingredient's action site makes it challenging to acquire an optimal synergism. Herein, a dual-pH responsive hybrid polymeric micelle system, HNP(αPDL1_6.9, Dox_5.3), is constructed as a proof-of-concept for the spatial cooperativity in chemo-immunotherapy. HNP retains the inherent pH-transition of each polymer, with stepwise disassembly under discrete pH thresholds. Within weakly acidic extracellular tumor environment, αPDL1 is first released to block the checkpoint on cell membranes. The remaining intact Doxorubicin-loaded micelle NP(Dox)_5.3 displays significant tropism toward tumor cells and releases Dox upon lysosomal pH for efficient tumor immunogenic cell death without immune toxicity. This sequential-released pattern boosts DC activation and primes CD8⁺ T cells, leading to enhanced therapeutic performance than single agent or an inverse-ordered combination in multiple murine tumor models. Using HNP, the indispensable role of conventional type 1 DC (cDC1) is identified in chemo-immunotherapy. A co-signature of cDC1 and CD8 correlates with cancer patient survival after neoadjuvant Pembrolizumab plus chemotherapy in clinic. This study highlights spatial cooperativity of chemo- and immuno-agents in immunoregulation and provides insights into the rational design of drug combination for future nanotherapeutics development.

中文翻译：

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阐明连续双 pH 响应药物递送系统在化学免疫治疗中的空间协同性

通过纳米技术将免疫检查点阻断与化疗相结合在安全性和有效性方面具有广阔的前景。然而，每种成分作用位点的独特亚细胞分布使得获得最佳协同作用具有挑战性。在此，构建了双 pH 响应杂化聚合物胶束系统 HNP（αPDL1 _6.9，Dox _5.3），作为化学免疫疗法中空间协同性的概念验证。 HNP 保留了每种聚合物固有的 pH 转变，并在离散 pH 阈值下逐步分解。在弱酸性细胞外肿瘤环境中，αPDL1首先被释放以阻断细胞膜上的检查点。剩余的完整负载阿霉素的胶束 NP(Dox) _5.3对肿瘤细胞表现出显着的趋向性，并在溶酶体 pH 值时释放 Dox，从而有效地杀死肿瘤免疫原性细胞，而没有免疫毒性。这种顺序释放模式可增强 DC 激活并启动 CD8 ⁺ T 细胞，从而在多个小鼠肿瘤模型中比单一药物或逆序组合提高治疗效果。使用 HNP，确定了传统 1 型 DC (cDC1) 在化学免疫治疗中不可或缺的作用。 cDC1 和 CD8 的共同特征与临床新辅助 Pembrolizumab 加化疗后癌症患者的生存率相关。这项研究强调了化学药物和免疫药物在免疫调节中的空间协同性，并为未来纳米治疗药物开发的合理设计药物组合提供了见解。