IL7R mRNA therapy enhances antitumor T cell immunity and suppresses tumor growth in preclinical tumor models

Abstract

Abstract Background Interleukin-7 receptor (IL7R) signaling is critical for T-cell survival, homeostasis, and immune function, but the therapeutic potential of increasing IL7R expression through messenger RNA (mRNA) delivery remains poorly defined. We investigated whether IL7R mRNA therapy could enhance antitumor immunity and improve tumor control in preclinical cancer models. Methods IL7R mRNA formulated in lipid nanoparticles (LNPs) was administered by combined intratumoral and intravenous injection in syngeneic B16 melanoma and Lewis lung carcinoma (LLC) models, with empty LNPs included as vehicle controls. Therapeutic efficacy, IL7R expression, immune responses, transcriptomic remodeling, T-cell receptor (TCR) repertoire changes, and treatment tolerability were evaluated using complementary molecular, immunological, and sequencing approaches. Results IL7R mRNA treatment increased IL7R transcript and protein levels in tumor-bearing mice, whereas empty LNPs did not produce comparable increases. Treatment increased tumor-infiltrating CD8 T-cell frequencies, suppressed tumor growth and prolonged survival in both B16 and LLC models; empty LNP controls did not reproduce the therapeutic effect. Cytokine and transcriptomic analyses showed treatment-associated activation of inflammatory, T-cell, interferon, and antigen-receptor signaling programs. TCR sequencing further demonstrated increased repertoire diversity and reduced clonal dominance following IL7R mRNA treatment. No obvious body-weight loss or marked changes in serum alanine aminotransferase, aspartate aminotransferase, or creatinine were observed under the tested conditions. Conclusions IL7R mRNA therapy increases IL7R expression and is associated with enhanced T-cell antitumor responses, tumor growth suppression, improved survival, and remodeling of the tumor immune environment. These findings support further mechanistic and preclinical evaluation of IL7R mRNA-based cancer immunotherapy.