Targeted delivery of T-cell agonists for enhancing immunotherapy

The T-cell agonist, l-arginine (L-arg), can act as an efficient antitumor T-cell response and improve antitumor immune activity. However, the low L-arg concentration in the tumor markedly inhibits the antitumor responses of immune checkpoint inhibitors. Furthermore, no method is currently available for increasing tumor L-arg levels locally. To overcome this challenge, we engineered a platelet (PLTs)-based drug carrier system (L-arg@PLTs) for tumor-targeted delivery and intratumoral release for locally increasing intratumoral L-arg levels. The PLTs drug delivery system can circulate freely in the blood until they are activated by the tumor, and recruit more L-arg@PLTs for targeted release of their content, which could increase the local L-arg concentration in the tumor. L-arg promotes T lymphocyte proliferation in tumor tissues, and T lymphocytes can inhibit tumor cell growth. L-arg acts synergistically with PD-1 inhibitors to inhibit tumor proliferation. Although this method cannot currently be used in clinics because of the limited source of human L-arg and safety-related issues in humans, this study provides a novel insight for tumor treatment. When combined with immunotherapy, this drug delivery system has produced a significant synergistic effect on malignant tumor treatment and offers a new strategy for targeted treatment in immunotherapy.