3M-052 combined inhibitory anti-TNFR2 synergistically suppresses colon cancer progression

Introduction: Immunotherapy is considered the most promising approach for achieving complete tumor clearance in cancer treatment. However, monotherapy has demonstrated limited clinical efficacy, leading to a growing consensus that combination immunotherapy-activating the immune system through multiple pathways-appears to be the optimal strategy for enhancing therapeutic outcomes. In this study, we investigated the efficacy and underlying mechanisms of the combination immunotherapy MT-comprising the TLR7/8 agonist 3M-052 and the inhibitory anti-TNFR2 antibody-in colon cancer (CRC). Methods: A CRC mouse model was established and divided into four treatment groups: the control group, the 3M-052 group, the anti-TNFR2 group, and the MT group. Tumour growth was monitored every three days. Flow cytometry was used to analyse the levels of CD8+ T cells and regulatory T cells (Tregs) in tumour tissue, as well as the differentiation of central memory T cells (Tcm) in the tumor-draining lymph nodes (TdLNs). Results: The results revealed that the combination therapy MT promoted CD8+ T cell infiltration and reduced Tregs level within the tumor, effectively suppressed colon cancer growth in mice, and induced long-term syngeneic tumor control by enhancing the differentiation of Tcm in TdLNs. Compared with monotherapy, combination therapy MT demonstrated a superior capacity to induce the differentiation of central memory CD8+ and CD4+ T cells in TdLNs, an effect that appears to be primarily mediated by 3M-052. Discussion: This study demonstrates that the combination of 3M-052 and the anti-TNFR2 antibody exerts a synergistic effect, effectively inhibiting CRC progression and inducing long-term immune memory. Overall, these findings support the view that MT combination therapy represents a potentially effective strategy.