Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy

Abstract

Although oncolytic adenoviruses are widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains to be studied. Here, we demonstrate that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, thymosin alpha 1 (Tα1) reprograms “M2-like” TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADV Tα1 is constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8 + T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing oncolytic engineered adenoviruses. • ADV-infected tumor cells induce M2 polarization of TAMs, requiring direct cell contact • Thymosin alpha 1 (Tα1) improves the antitumor efficacy of oncolytic adenovirus • Tα1 orchestrates TAMs to drive antitumor CD8 + T cell immunity during OV treatment • Potential clinical translation of ADV Tα1 in improving outcomes for patients with cancer Liu et al. report that the type V adenovirus (ADV) induces M2 polarization of tumor-associated macrophages in a direct cell contact-dependent manner. Tα1 reprograms ADV-induced “M2-like” macrophages toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity.

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