Thymosin α1 Boosts Cancer Immunity by Reprogramming Macrophages in Adenovirus Therapy

Oncolytic adenoviruses are promising cancer therapies that selectively infect and destroy tumor cells, while also stimulating anti-tumor immune responses. However, their efficacy is often limited by the tumor microenvironment, which can promote an immunosuppressive state, including the M2 polarization of macrophages. These M2 macrophages hinder effective anti-tumor immunity, and strategies to reverse this M2 polarization to enhance oncolytic adenovirus therapy are urgently needed to improve patient outcomes.

The study revealed that Thymosin α1 significantly enhanced the anti-tumor effects of oncolytic adenovirus (OAV), demonstrating a potent synergistic therapeutic outcome. Co-administration of Thymosin α1 with OAV led to a remarkable 65% reduction in average tumor volume compared to OAV alone (p<0.001), and a 43% reduction compared to Thymosin α1 monotherapy, significantly prolonging survival by 30% over OAV treatment. Mechanistically, Thymosin α1 treatment effectively reversed OAV-induced M2 macrophage polarization within the tumor microenvironment, decreasing the proportion of immunosuppressive M2-like macrophages (identified by CD206+ expression) by 55% compared to OAV-treated controls. This crucial phenotypic shift was accompanied by a 2.8-fold increase in pro-inflammatory M1-like macrophages (CD86+ expression) and a robust 3.5-fold increase in tumor-infiltrating cytotoxic CD8+ T cells, indicating a powerful redirection towards an anti-tumor immune response. Furthermore, the combination therapy resulted in a 2-fold increase in the expression of key pro-inflammatory cytokines like IFN-γ and TNF-α and a 1.7-fold decrease in immunosuppressive IL-10 within the tumors, confirming a more favorable immune milieu.