Thymopentin enhances adenoviral oncolytic therapy by regulating macrophages and CD8⁺ T cells

Oncolytic viruses are cancer therapies that selectively replicate in tumors, deliver therapeutic genes, and stimulate immune responses. Combining these viruses with immune-boosting agents could enhance their effectiveness. Thymopentin (TP5), an immune-modulating peptide, may enhance the antitumour efficacy of ADV.

We tested TP5 combined with adenovirus type 5 in tumor models, measuring tumor growth and immune changes using flow cytometry and antibody-based cell depletion. A modified oncolytic adenovirus producing TP5 (ADV-TP5) was created using gene editing and tested in mice and human immune cell-engrafted tumor models. TP5 was also combined with herpes simplex virus and vaccinia virus.

Here we show that combining adenovirus (ADV) with thymopentin (TP5) reprograms the tumor microenvironment and enhances antitumor efficacy in xenograft models. ADV + TP5 increases proinflammatory macrophages and cytotoxic CD8⁺ T-cell infiltration while stimulating long-term immune memory. We further engineer an oncolytic adenovirus expressing TP5 (ADV-TP5), which demonstrates superior tumor suppression compared to unmodified ADV in mice and human immune cell-engrafted models. TP5 also amplifies responses when combined with other oncolytic viruses (e.g., herpes simplex virus, vaccinia virus), supporting its role as a broad-spectrum adjuvant for clinical virotherapies.

TP5 strengthens oncolytic virotherapy by orchestrating macrophages and CD8⁺ T cells to attack tumors. Its dual use, as a combination drug or engineered into viruses, offers a practical strategy to improve clinical outcomes. This approach provides a low-cost method to amplify oncolytic virus efficacy and inspires designs where single therapies mimic combination effects, advancing accessible cancer immunotherapy.