Nanogel-delivered Caerin 1.1/1.9 peptides reprogram tumor microenvironment, boosting anti-tumor immunity and survival.

Host-defence peptides (HDPs) like caerin 1.1 and 1.9 show promise for cancer therapy due to direct cytotoxicity and immunomodulatory effects. However, their clinical utility is severely hampered by rapid degradation and poor intratumoral retention, limiting sustained therapeutic concentrations. This study addresses these delivery challenges, aiming to unlock the full potential of HDPs by improving their pharmacokinetics within the tumor microenvironment (TME) and enhancing their immune-dependent anti-tumor mechanisms. The goal is to achieve durable anti-cancer responses by overcoming the inherent instability of these potent peptides.

Researchers developed a self-assembling nanogel (NAP-GFFY) to encapsulate caerin 1.1 and 1.9 (F1/F3) peptides, forming F1/F3-NAP-GFFY. They tested its efficacy against free peptide in immune-competent, immunodeficient, and PBMC-humanized mouse models of tumor growth. Local intratumoral administration was used, comparing nanogel-delivered peptides to free peptides. Primary endpoints included tumor growth suppression, intratumoral peptide retention, and survival. Mechanistic insights were gained via integrated transcriptomic, proteomic, and metabolomic analyses of the tumor microenvironment.

The F1/F3-NAP-GFFY nanogel formed stable supramolecular nanofibrous structures, demonstrating sustained release and stability under acidic, enzymatic, and thermal stress conditions. Caerin peptides suppressed tumor growth in immune-competent and PBMC-humanized mice but showed minimal activity in immunodeficient mice, confirming a predominantly immune-dependent mechanism.

Nanogel-mediated delivery significantly prolonged intratumoral peptide retention following local administration, leading to enhanced tumor suppression and prolonged survival compared to free peptide treatment. Integrated transcriptomic, proteomic, and metabolomic analyses revealed coordinated reprogramming of the tumor microenvironment. This included activation of antigen processing and presentation pathways, interferon-responsive signaling, cytotoxic immune programs, and inflammasome-associated responses. Concurrent metabolic alterations, such as lipid remodeling, mitochondrial β-oxidation, and redox regulation, indicated adaptive immunometabolic restructuring. These changes were accompanied by increased infiltration of CD4+ and CD8+ effector T cells, expansion of dendritic cell populations, and reduction of immunosuppressive monocytic MDSCs in tumors and draining lymph nodes.