免疫原性细胞死亡（ICD）诱导剂在肿瘤的积聚和分布不足，以及抗肿瘤免疫应答的低效，严重限制了肿瘤免疫治疗的疗效。肿瘤相关成纤维细胞（TAFs）在肿瘤细胞外基质（ECM）重塑和免疫逃避中起着重要作用。通过调控TAFs来重编程肿瘤免疫抑制性微环境可能是增强ICD效应和完全消除肿瘤的一种有希望的途径。本研究开发了由TAFs衍生的胰蛋白酶印记纳米颗粒（DMSN@MIPs），用于调节TAFs并提高多柔比星脂质体（DOX/LIP）的肿瘤免疫治疗效果。我们发现，由肥大细胞分泌的胰蛋白酶（TPS）通过转录活化TAFs，使其处于增强表达成纤维母细胞活化标记α-平滑肌肌动蛋白（α-SMA）的激活状态，从而支持肿瘤生长。DMSN@MIPs可被用作人工抗体，有效中和TPS，减少TAFs的活化，促进DOX/LIP的肿瘤内穿透，并增强DOX/LIP引发的ICD效应。此外，联合治疗体系重塑了免疫抑制性微环境，不仅显著上调免疫细胞（DC细胞、CD8+T细胞、NK细胞），还显著下调免疫抑制细胞（Treg细胞、MDSCs细胞）。我们的结果支持DMSN@MIPs可以成为改善肿瘤免疫治疗中ICD效果的一种有希望的方法。版权所有 © 2023. 由Elsevier B.V.出版。

Insufficient tumor accumulation and distribution of immunogenic cell death (ICD) inducer as well as low antitumor immunity severely restrict the therapeutic efficacy of tumor immunotherapy. Tumor associated fibroblasts (TAFs) are important in tumor extracellular matrix (ECM) remodeling and immune evasion. Reprogramming tumor immunosuppressive microenvironment via TAFs regulation might present a promising way for enhanced ICD effect and complete tumor elimination. In this study, TAFs derived tryptase imprinted nanoparticles (DMSN@MIPs) are developed to modulate TAFs and improve tumor immunotherapy effect of doxorubicin liposomes (DOX/LIP). Tryptase (TPS), secreted by mast cells, are found to support tumor growth via transcriptionally activating TAFs to an activated state with increased expression of fibroblast activation marker α-smooth muscle actin (α-SMA). DMSN@MIPs canbe used as artificial antibodies, which effectively neutralize TPS, reduce TAFs activation, promote intra-tumor penetration of DOX/LIP and enhance ICD effect induced by DOX/LIP. In addition, the combined administration system remodels immunosuppressive microenvironment, which not only significantly up-regulates immune cells (DC cells, CD8+T cells, NK cells), but also significantly down-regulates immunosuppressive cells (Treg cells, MDSCs cells). Our results support the DMSN@MIPs canbe a promising approach to improve ICD efficacy in cancer immunotherapy.Copyright © 2023. Published by Elsevier B.V.