Pyruvate Kinase M2‐Responsive Release of Paclitaxel and Indoleamine 2,3‐Dioxygenase Inhibitor for Immuno‐Chemotherapy of Nonsmall Cell Lung Cancer

作者：Haisi Wu, Xianbao Sun, Kaiming Li, Jinyu Li, Hui Jiang, Dan Yan, Lin Ya, Yan Ding, Yawen Lu, Xiaole Zhu, Xufeng Chen, Xiaolin Li, Gaolin Liang, Huae Xu · 发表于：Advanced Science · 年份：2024 · DOI：10.1002/advs.202409790 · 被引用次数：8 · 研究领域：Epigenetics and DNA Methylation、Nanoplatforms for cancer theranostics、Immune cells in cancer

Abstract Paclitaxel (PTX) is a first‐line chemotherapeutic drug for non‐small cell lung cancer (NSCLC) but it can induce indoleamine 2,3‐dioxygenase (IDO) activation, which severely lowers down its immuno‐chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap–Phe–Phe–Phe–Lys–Ser–Thr–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap‐T ), which co‐assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap‐T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap‐T is gradually converted to Nap–Phe–Phe–Phe–Lys–Ser–Thr(H 2 PO 3 )–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap‐Tp ), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno‐chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap‐T enhances the infiltration of tumor‐infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor‐draining lymph nodes, thus enhancing the immuno‐chemotherapy of PTX toward NSCLC. With this PKM2‐responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future.