Liu Yibin, Chen Xiayun, Zhang Wei, Yu Baixue, Cen Yi, Liu Qianqian, Tang Youzhi, Li Shiying
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
Acta Biomater. 2025 May 1;197:400-415. doi: 10.1016/j.actbio.2025.03.049. Epub 2025 Mar 26.
The therapeutic efficacy of immune checkpoint blockade (ICB) is critically compromised by inadequate T lymphocyte infiltration, low T cell-induced pro-inflammatory responses, and the accumulation of immunosuppressive cells within the tumor microenvironment (TME). In this work, a chimeric peptide-engineered immunomodulatory nanomedicine (designated as CXNP-CeBM) is developed for photodynamic amplified ICB therapy against breast cancer. CXNP-CeBM is composed of a CXCR4-targeting peptide ((C)-KLGASWHRPDK) loaded with the photosensitizer of Ce6 and the PD-1/PD-L1 inhibitor of BMS8. CXNP-CeBM specifically recognizes CXCR4 on breast cancer, thus suppressing CXCR4-mediated signaling pathways and enhancing the intracellular delivery of therapeutic agents. The photodynamic therapy (PDT) of CXNP-CeBM damages primary tumor cells to initiate immunogenic cell death (ICD), leading to the release of high mobility group box 1 (HMGB1) and the exposure of calreticulin (CRT). Simultaneously, the interruption of CXCR4 signaling reduces tumor fibrosis, promotes T-cell infiltration, and decreases the number of immunosuppressive cells, thereby enhancing the immunotherapeutic effect of ICB. Treatment with CXNP-CeBM would activate systemic anti-tumor immunity, leading to effective inhibition of both primary and lung metastatic tumors, while maintaining low systemic toxicity. This work provides a reliable strategy for the delivery of multi-synergistic agents, effectively activating breast cancer immunity through a multifaceted mechanism. STATEMENT OF SIGNIFICANCE: Although immune checkpoint blockade (ICB) has shown great potential for malignant tumor therapy, its efficacy is compromised by immunosuppressive microenvironments. Herein, a CXCR4-targeted immunomodulatory nanomedicine (CXNP-CeBM) was constructed for photodynamic amplified ICB therapy of breast cancer. CXNP-CeBM could selectively deliver photosensitizers and PD-1/PD-L1 inhibitors to breast cancer cells that overexpressed the chemokine receptor CXCR4, while interrupting CXCR4 signaling to reduce tumor fibrosis, promote T-cell infiltration, and decrease the number of immunosuppressive cells. Moreover, CXNP-CeBM induced photodynamic therapy to trigger immunogenic cell death while downregulating the PD-L1 level to destroy immune evasion mechanisms, thus activating immunological cascades to treat both primary and lung metastatic tumors. This study provided a multi-synergistic strategy for breast cancer immunotherapy through a multifaceted mechanism.
免疫检查点阻断（ICB）的治疗效果受到肿瘤微环境（TME）中T淋巴细胞浸润不足、T细胞诱导的促炎反应低下以及免疫抑制细胞积累的严重影响。在这项工作中，开发了一种嵌合肽工程化免疫调节纳米药物（命名为CXNP-CeBM），用于光动力增强的ICB治疗乳腺癌。CXNP-CeBM由负载Ce6光敏剂和BMS8的PD-1/PD-L1抑制剂的CXCR4靶向肽（(C)-KLGASWHRPDK）组成。CXNP-CeBM特异性识别乳腺癌上的CXCR4，从而抑制CXCR4介导的信号通路并增强治疗剂的细胞内递送。CXNP-CeBM的光动力疗法（PDT）损伤原发性肿瘤细胞以引发免疫原性细胞死亡（ICD），导致高迁移率族蛋白B1（HMGB1）释放和钙网蛋白（CRT）暴露。同时，CXCR4信号的中断减少肿瘤纤维化，促进T细胞浸润，并减少免疫抑制细胞数量，从而增强ICB的免疫治疗效果。用CXNP-CeBM治疗会激活全身抗肿瘤免疫，有效抑制原发性和肺转移肿瘤，同时保持低全身毒性。这项工作为多协同剂的递送提供了可靠策略，通过多方面机制有效激活乳腺癌免疫。意义声明：尽管免疫检查点阻断（ICB）在恶性肿瘤治疗中显示出巨大潜力，但其疗效受到免疫抑制微环境的影响。在此，构建了一种CXCR4靶向免疫调节纳米药物（CXNP-CeBM）用于乳腺癌的光动力增强ICB治疗。CXNP-CeBM可以选择性地将光敏剂和PD-1/PD-L1抑制剂递送至过表达趋化因子受体CXCR4的乳腺癌细胞，同时中断CXCR4信号以减少肿瘤纤维化，促进T细胞浸润，并减少免疫抑制细胞数量。此外，CXNP-CeBM诱导光动力疗法触发免疫原性细胞死亡，同时下调PD-L1水平以破坏免疫逃逸机制，从而激活免疫级联反应来治疗原发性和肺转移肿瘤。本研究通过多方面机制为乳腺癌免疫治疗提供了一种多协同策略。
