近日，湖南大学袁林团队报道了反应性光敏剂前体逆转药物诱导的继发性免疫抑制。相关论文于2025年11月6日发表在《美国化学会志》上。

药物治疗是抑制肿瘤细胞增殖的常用方法，但往往会同时诱导继发性免疫抑制。通过光敏将肿瘤相关巨噬细胞（TAMs）从M2表型重编程为M1表型提供了一种很有前景的策略，可以缓解免疫抑制的肿瘤微环境，这可能是逆转继发性免疫抑制的有效途径。然而，由于巨噬细胞特异性不足和不理想的光敏性，目前的光敏剂的疗效有限。

为了解决这些挑战，研究组在此报告了一种邻近驱动策略，该策略优化了光敏剂前体（PPs）相对于过表达酶活性中心的空间定位，大大提高了PPs在M2巨噬细胞中的激活效率和选择性。同时，通过光敏剂性能的综合筛选，研究组开发了一种新型PP (NP-YB-5)，与现有的免疫佐剂和早期反应性前体（60%）相比，它在诱导巨噬细胞极化方面表现出更高的功效（72.1%）。

更重要的是，NP-YB-5介导的光疗不仅可以消除继发性免疫抑制的原发肿瘤，还可以抑制远端（转移）肿瘤的进展，统计治愈率为85%。该工作为开发巨噬细胞介导的光敏化的有效分子工具提供了一种新的设计范式，为克服药物诱导的肿瘤继发性免疫抑制提供了一种有前景的方法。

附：英文原文

Title: Responsive Photosensitizer Precursors Reverse Drug-Induced Secondary Immunosuppression

Author: Shan Zuo, Huiyi Liu, Gangwei Jiang, Yushi Chen, Tianbing Ren, Zhixuan Zhou, Xiao-Bing Zhang, Lin Yuan

Issue&Volume: November 6, 2025

Abstract: Pharmacological treatments, common methods for inhibiting tumor cell proliferation, often concurrently induce secondary immunosuppression. Reprogramming tumor-associated macrophages (TAMs) from an M2 to M1 phenotype via photosensitization offers a promising strategy to relieve the immunosuppressive tumor microenvironment, which may serve as an effective approach to reverse secondary immunosuppression. However, the efficacy of current photosensitizers is limited due to the insufficient macrophage specificity and suboptimal photosensitivity. To address these challenges, we here reported a proximity-driven strategy that optimizes the spatial positioning of photosensitizer precursors (PPs) relative to the active center of overexpressed enzymes, substantially enhancing the activation efficiency and selectivity of PPs in M2 macrophages. Simultaneously, through the integrated screening of photosensitizer performance, we developed a novel PP (NP-YB-5) that demonstrates superior efficacy (72.1%) in inducing macrophage polarization compared to both current immune adjuvants and earlier-generation responsive precursors (<60%). More importantly, phototherapy mediated by NP-YB-5 not only eliminates primary tumors exhibiting secondary immunosuppression but also inhibits the progression of distal (metastatic) tumors, achieving a statistical cure rate of 85%. Our work presents a novel design paradigm for the development of potent molecular tools in macrophage-mediated photosensitization, offering a promising approach for overcoming drug-induced secondary immunosuppression of tumors.

DOI: 10.1021/jacs.5c15227

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c15227