胰腺癌组织中致密的基质屏障阻碍了化疗药物和治疗抗体的瘤内递送和分布，导致化学免疫治疗反应不佳。我们设计了一种多靶点 pH 敏感脂质体，将顺铂 (Pt) 封装在其水核中（表示为 ATF@Pt Lps），并对胰腺癌细胞、肿瘤相关巨噬细胞和癌症相关成纤维细胞中的 uPAR 受体表现出高亲和力。 ATF@Pt Lps 的全身给药能够克服中央基质细胞屏障并将药物有效输送到肿瘤细胞中，从而在 Panc02 细胞衍生的移植肿瘤小鼠模型中产生强烈的治疗反应。更重要的是，ATF@Pt Lps 胶原蛋白的降解有助于 CD8 T 细胞浸润到肿瘤中，并增强抗 PD-1 单克隆抗体的积累。此外，Pt对肿瘤细胞的杀伤还会导致肿瘤抗原的释放，从而促进免疫细胞的增殖，特别是CD83细胞、Th1 CD4细胞和CD8细胞毒性T细胞，从而将免疫评分“冷”的胰腺癌转化为促免疫“热”肿瘤。进一步与免疫检查点药物、抑制 PD-1 的抗 PD-1 抗体组合，可以增强肿瘤特异性细胞毒性 T 细胞反应。因此，ATF@Pt Lps 表现出多靶向、控制药物释放、基质破坏、增强渗透、杀死癌细胞、改变免疫抑制微环境和增强免疫力。这项研究为进一步开发 ATF@Pt Lps 和抗 PD-1 抗体的组合以有效治疗胰腺癌提供了重要的机制信息。

The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore "cold" pancreatic cancer into a pro-immune "hot" tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.