Breast cancer recurrence is the greatest contributor to patient death. As the immune system has a long-term immune memory effect, immunotherapy has great potential for preventing cancer recurrence. However, cancer immunotherapy is often limited due to T cell activation being blocked by insufficient tumor immunogenicity and the complex immunosuppressive tumor microenvironment. Here we show a tumor acidity activatable and Ca²⁺-assisted immuno-nanoagent to synergistically promote T cell activation and enhance cancer immunotherapy. When the immuno-nanoagent reaches the acidic tumor microenvironment, the CaCO₃ matrix disintegrates to release immune stimulants (CpG ODNs and IDOi) and Ca²⁺. CpG ODNs are responsible for triggering dendritic cell maturation to increase the immunogenicity for activation of T cells. And IDOi can inhibit the oxidative catabolism of tryptophan to kynurenine for preventing T-cell anergy and apoptosis. Due to the complexity of the immunosuppressive microenvironment, it is difficult to restore T cell activation by inhibiting only one pathway. Fortunately, the released Ca²⁺ can promote the activation and proliferation of T cells with the support of the immune stimulants. In vivo experiments demonstrate that our Ca²⁺-assisted immuno-nanoagent can significantly suppress tumor progression and protect mice from tumor rechallenge due to the long-term memory effect. This immunotherapeutic strategy may provide more possibilities for clinical applications such as treating cancer and preventing relapse.

中文翻译：

---

可激活肿瘤酸度和Ca2 +辅助的免疫纳米剂可增强乳腺癌治疗并抑制癌症复发

乳腺癌复发是导致患者死亡的最大原因。由于免疫系统具有长期的免疫记忆作用，因此免疫疗法具有预防癌症复发的巨大潜力。然而，由于T细胞活化被不足的肿瘤免疫原性和复杂的免疫抑制肿瘤微环境所阻断，因此癌症免疫疗法常常受到限制。在这里，我们显示了可激活的肿瘤酸度和Ca ²⁺辅助免疫纳米剂，以协同促进T细胞活化并增强癌症免疫疗法。当免疫纳米剂到达酸性肿瘤微环境时，CaCO ₃基质分解以释放免疫刺激剂（CpG ODN和IDOi）和Ca ²⁺。CpG ODN负责触发树突状细胞成熟，以增强T细胞活化的免疫原性。IDOi可以抑制色氨酸向犬尿氨酸的氧化分解代谢，从而防止T细胞无反应性和凋亡。由于免疫抑制微环境的复杂性，仅通过抑制一条途径就很难恢复T细胞活化。幸运的是，在免疫刺激剂的支持下，释放的Ca ²⁺可以促进T细胞的活化和增殖。体内实验表明，我们的Ca ²⁺辅助的免疫纳米剂由于具有长期记忆效应，因此可以显着抑制肿瘤进展并保护小鼠免受肿瘤再攻击。这种免疫治疗策略可能为临床应用提供更多可能性，例如治疗癌症和预防复发。