DataSheet_1_Self-assembled albumin nanoparticles induce pyroptosis for photodynamic/photothermal/immuno synergistic therapies in triple-negative breast cancer.docx

Triple-negative breast cancer (TNBC) is characterized by a high degree of malignancy, early metastasis, limited treatment, and poor prognosis. Immunotherapy, as a new and most promising treatment for cancer, has limited efficacy in TNBC because of the immunosuppressive tumor microenvironment (TME). Inducing pyroptosis and activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity have become an emerging strategy for enhancing tumor immunotherapy. In this study, albumin nanospheres were constructed with photosensitizer-IR780 encapsulated in the core and cGAS–STING agonists/H2S producer-ZnS loaded on the shell (named IR780-ZnS@HSA). In vitro, IR780-ZnS@HSA produced photothermal therapy (PTT) and photodynamic therapy (PDT) effects. In addition, it stimulated immunogenic cell death (ICD) and activated pyroptosis in tumor cells via the caspase-3–GSDME signaling pathway. IR780-ZnS@HSA also activated the cGAS–STING signaling pathway. The two pathways synergistically boost immune response. In vivo, IR780-ZnS@HSA + laser significantly inhibited tumor growth in 4T1 tumor-bearing mice and triggered an immune response, improving the efficacy of the anti-APD-L1 antibody (aPD-L1). In conclusion, IR780-ZnS@HSA, as a novel inducer of pyroptosis, can significantly inhibit tumor growth and improve the efficacy of aPD-L1.

三阴性乳腺癌（Triple-negative breast cancer, TNBC）以高度恶性、早期转移、治疗手段有限及预后不良为典型特征。免疫治疗作为一种新兴且最具前景的癌症治疗手段，却因免疫抑制性肿瘤微环境（immunosuppressive tumor microenvironment, TME）在TNBC中疗效受限。诱导细胞焦亡并激活环状GMP-AMP合酶/干扰素基因刺激因子（cGAS/STING）信号通路以上调先天免疫，已成为增强肿瘤免疫治疗的新兴研究策略。本研究构建了一款白蛋白纳米球：其内核封装光敏剂IR780，外壳负载cGAS-STING激动剂与硫化氢供体ZnS，将其命名为IR780-ZnS@HSA。体外实验中，IR780-ZnS@HSA可同时发挥光热治疗（photothermal therapy, PTT）与光动力治疗（photodynamic therapy, PDT）效应；此外，其可通过半胱天冬氨酸蛋白酶3-GSDME信号通路诱导肿瘤细胞发生免疫原性细胞死亡（immunogenic cell death, ICD）并激活细胞焦亡。IR780-ZnS@HSA还可直接激活cGAS/STING信号通路，两条通路协同增强机体免疫应答。体内实验结果显示，IR780-ZnS@HSA联合激光照射可显著抑制4T1荷瘤小鼠的肿瘤生长，触发抗肿瘤免疫应答，有效提升抗PD-L1抗体（aPD-L1）的治疗效果。综上，IR780-ZnS@HSA作为一种新型细胞焦亡诱导剂，可显著抑制肿瘤生长并增强抗PD-L1抗体的治疗效能。