Tumor microenvironment reprogramming combined with immunogenic enhancement by nanoemulsions potentiates immunotherapy

• Published in: Journal of nanobiotechnology Vol. 22; no. 1; p. 154
• Main Authors: Shen, Wenqi, Li, Yecheng, Yang, Ziyi, Li, Wenjing, Cao, Yi, Liu, Yilin, Wang, Zheng, Pei, Renjun, Xing, Chungen
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.04.2024; BioMed Central; BMC
• Subjects: Analysis; Antibodies; Antineoplastic Agents - pharmacology; Antitumor activity; Bioavailability; Cancer; Cancer therapies; Cancer-associated fibroblasts; Cell death; Cell Line, Tumor; Colon cancer; Colorectal cancer; Colorectal Neoplasms; Complications and side effects; CTLA-4 protein; Cytokines; Cytotoxicity; Fibroblasts; Health aspects; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immunogenicity; Immunotherapy; Infiltration; Intratumoral penetration; Lymphocytes; Lymphocytes T; Medical research; Metastases; Molecular dynamics; Nanoemulsions; Nanoparticles; Neoplasms - drug therapy; Nitric oxide; Patient outcomes; Peptides; Sensitivity enhancement; Stroma; T cells; Tumor immunotherapy; Tumor Microenvironment; Tumors; China; United States > US; Cancer-associated fibroblasts; Intratumoral penetration; Tumor immunotherapy; Colon cancer; Tumor microenvironment
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-024-02401-y

The combination of immune checkpoint inhibitors and immunogenic cell death (ICD) inducers has become a promising strategy for the treatment of various cancers. However, its efficacy remains unmet because of the dense stroma and defective vasculatures in the tumor microenvironment (TME) that restricts the intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Herein, cancer-associated fibroblasts (CAFs)-targeted nanoemulsions are tailored to combine the ICD induction and the TME reprogramming to sensitize checkpoint blockade immunotherapy. Melittin, as an ICD inducer and an antifibrotic agent, is efficiently encapsulated into the nanoemulsion accompanied by a nitric oxide donor to improve its bioavailability and tumor targeting. The nanoemulsions exhibited dual functionality by directly inducing direct cancer cell death and enhancing the tumoral immunogenicity, while also synergistically reprogramming the TME through reversing the activated CAFs, decreasing collagen deposition and restoring tumor vessels. Consequently, these nanemulsions successfully facilitated the CTLs infiltration and suppressing the recruitment of immunosuppressive cells. A combination of AE-MGNPs and anti-CTLA-4 antibody greatly elicited a striking level of antitumor T-cell response to suppress tumor growth in CAFs-rich colorectal tumor models. Our work emphasized the integration of the ICD induction with simultaneous modulation of the TME to enhance the sensitivity of patients to checkpoint blockade immunotherapy.