Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers

TLDR

Tumor‑associated macrophages are typically M2‑polarized, promoting immunosuppression and tumor growth, and attempts to reprogram them to an M1 phenotype have been nonspecific and caused systemic inflammation. The study aims to develop a targeted nanocarrier that delivers mRNA for M1‑polarizing transcription factors to reprogram TAMs safely, enabling clinic‑based immunotherapy that avoids systemic immune disruption. The nanocarrier delivers in‑vitro‑transcribed mRNA encoding interferon‑regulatory factor 5 and its activating kinase IKKβ directly to TAMs, reprogramming them to an M1 phenotype without systemic toxicity. In ovarian, melanoma, and glioblastoma models, the nanoparticles reversed TAM immunosuppression, induced anti‑tumor immunity, promoted tumor regression, and were safe for repeated dosing.

Abstract

Abstract Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKβ reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.