Guo Guanhong, Ding Wenshuo, Li Fahui, Li Zhengbo, Qin Shuangfeng, Xu Guangzhao, Yue Xiangguo, Wang Xudong, Song Weiguo, Sun Wen, Zhong Wenda
School of Pharmacy, Shandong Second Medical University, Weifang 261053, People's Republic of China.
Weifang University of Science and Technology, Weifang 262700, People's Republic of China.
J Colloid Interface Sci. 2025 Nov;697:137980. doi: 10.1016/j.jcis.2025.137980. Epub 2025 May 24.
Due to population aging and lifestyle changes, the global tumor burden has increased, making tumor disease a significant challenge in public health. Recently, immunotherapy emerged as an effective approach for tumor treatment by activating and enhancing the body's immune system to precisely identify and attack tumor cells. However, its efficacy was limited by the "cold" immunosuppressive tumor microenvironment (ITME) and the tissue repair capabilities of tumors. To address this issue, we developed a dual-target ferroptosis immune-inducer, FTB@CC, which releases photosensitizer (PS), calcium (Ca), and Fe under weakly acidic conditions. Upon near-infrared (NIR) laser irradiation, PSs induced endoplasmic reticulum (ER) stress, producing large amounts of reactive oxygen species (ROS) and releasing significant quantities of damage-associated molecular patterns (DAMPs), which mediated immunogenic cell death (ICD). Simultaneously, Ca overload activates the inflammasome and amplifies cellular cytotoxicity for DAMPs release, eventually activating the ICD pathway. The supplementation of Fe increased iron storage within tumor cells and downregulated the expression of glutathione peroxidase 4 (GPX4), leading to the accumulation of lipid peroxides (LPO) and ultimately resulting in ferroptosis. This multi-level interaction strategy restructured the ITME and induced ICD, overcoming the limitations of single-agent therapies, and significantly enhancing the efficacy of anti-PD-L1 antibody (α-PD-L1) in suppressing tumor cell immune evasion. As a result, it promoted the infiltration of immune cells and inhibited both distal and proximal tumors. This nano-integrated ICD-ferroptosis co-inducer offers an intelligent strategy for effectively overcoming ITME, thereby providing a promising avenue for advanced immunotherapeutic interventions.
由于人口老龄化和生活方式的改变，全球肿瘤负担增加，使肿瘤疾病成为公共卫生领域的一项重大挑战。最近，免疫疗法作为一种有效的肿瘤治疗方法出现，通过激活和增强机体免疫系统来精确识别和攻击肿瘤细胞。然而，其疗效受到“冷”免疫抑制肿瘤微环境（ITME）和肿瘤组织修复能力的限制。为了解决这个问题，我们开发了一种双靶点铁死亡免疫诱导剂FTB@CC，它在弱酸性条件下释放光敏剂（PS）、钙（Ca）和铁（Fe）。在近红外（NIR）激光照射下，PS诱导内质网（ER）应激，产生大量活性氧（ROS）并释放大量损伤相关分子模式（DAMPs），介导免疫原性细胞死亡（ICD）。同时，Ca过载激活炎性小体并放大细胞毒性以释放DAMPs，最终激活ICD途径。Fe的补充增加了肿瘤细胞内的铁储存并下调了谷胱甘肽过氧化物酶4（GPX4）的表达，导致脂质过氧化物（LPO）积累并最终导致铁死亡。这种多层次相互作用策略重塑了ITME并诱导ICD，克服了单药治疗的局限性，并显著增强了抗PD-L1抗体（α-PD-L1）抑制肿瘤细胞免疫逃逸的疗效。结果，它促进了免疫细胞的浸润并抑制了远端和近端肿瘤。这种纳米整合的ICD-铁死亡共诱导剂为有效克服ITME提供了一种智能策略，从而为先进的免疫治疗干预提供了一条有前景的途径。
