Delivery of mRNA Encoding Interleukin-12 and a Stimulator of Interferon Genes Agonist Potentiates Antitumor Efficacy through Reversing T Cell Exhaustion

• Published in: ACS nano 2024-06, Vol.18 (24), p.15499-15516
• Main Authors: Wang, Bin, Tang, Maoping, Chen, Qijing, Ho, William, Teng, Yilong, Xiong, Xiaojian, Jia, Zhitong, Li, Xiuling, Xu, Xiaoyang, Zhang, Xue-Qing
• Format: Article
• Language: English
• ISSN: 1936-0851; 1936-086X; 1936-086X
• DOI: 10.1021/acsnano.4c00063

T cell exhaustion has emerged as a major hurdle that impedes the clinical translation of stimulator of interferon genes (STING) agonists. It is crucial to explore innovative strategies to rejuvenate exhausted T cells and potentiate the antitumor efficacy. Here, we propose an approach utilizing MSA-2 as a STING agonist, along with nanoparticle-mediated delivery of mRNA encoding interleukin-12 (IL-12) to restore the function of T cells. We developed a lipid nanoparticle (DMT7-IL12 LNP) that encapsulated IL12 mRNA. Our findings convincingly demonstrated that the combination of MSA-2 and DMT7-IL12 LNP can effectively reverse the exhausted T cell phenotype, as evidenced by the enhanced secretion of cytokines, such as tumor necrosis factor alpha, interferon gamma, and Granzyme B, coupled with reduced levels of inhibitory molecules such as T cell immunoglobulin and mucin domain-3 and programmed cell death protein-1 on CD8+ T cells. Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.