Limitation-circumventing and strength-capitalizing hydrogel potentiates durable antitumor immunity and robust...

Background: Radiotherapy (RT)-induced antitumor immunity has attracted extensive attention. However, such antitumor immunity often proves inadequate to combat metastatic and recurrent tumors in clinical practice. While hypoxia severely limits the initiation of adequate systemic antitumor immune responses, the strength of such responses is further compromised by the blockage of effector T cells, ultimately undermining the ability of RT to elicit a robust abscopal effect and durable immune memory. Methods: Hence, a limitation-circumventing strength-capitalizing hydrogel (UP) is developed to increase the efficacy of RT for a robust abscopal effect and durable antitumor immunity to cope with metastatic and recurrent tumors. Results: With single-administration and radiation treatments, UP efficiently generates oxygen in situ to circumvent the limitation of RT hypoxia. After such limitations are overcome, the tumor-killing capacity of RT is significantly promoted, resulting in strong antitumor immune responses. Moreover, UP further inhibits immune checkpoints to reinvigorate effector T cells, capitalizing on the strength of RT-induced antitumor immune responses. With such strength-capitalization, RT-induced transient immune responses are amplified to systemic immunity, triggering a robust abscopal effect to eliminate distant metastasis and establishing durable immune memory against recurrence. Conclusions: Consequently, UP potentiates the antitumor immunity of RT through circumventing the hypoxia barrier and capitalizing on immune activation. Our study provides new insights into RT enhancement.