Hypoxia, a state of low oxygen tension, is one of the major obstacles in the treatment of solid tumors due to its inhibitory effect on cytotoxic immune cells. Targeting hypoxia-driven immunosuppression is a promising approach to prevent tumor escape from immunosurveillance. Biomaterials with a capacity to produce oxygen and be delivered near a tumor bed represent a viable strategy for reversing local hypoxia. This approach could boost effector functions of antitumor T cells and potentially reinforce current cancer immunotherapies. Recently, we engineered injectable oxygen-generating biomaterials, known as cryogels. Oxygen-generating cryogels (O2-cryogels), with their unique physical features, including mechanical robustness and syringe injectability, were designed to release oxygen in a controlled and sustained fashion. We found that local oxygenation from O2-cryogels downregulates hypoxia-inducible gene expression in hypoxic tumor cells and reduced the accumulation of immunosuppressive metabolites such as extracellular adenosine. Strikingly, O2-cryogels release the break on the tumoricidal function of hypoxic T cells against melanoma in a very short time (&lt; 4h). Mechanistically, O2-cryogels i) enhance T cell–tumor cell interactions; ii) increase T cell-mediated production of cytotoxic proteins (perforin and granzyme B) fatal to tumor cells; and, as a result; iii) restore the killing ability of antigen-specific T cells. Collectively, O2-cryogels provide a unique platform to expand our understanding on how hypoxia affects immune cells and may leverage emergent cancer immunotherapies to circumvent hypoxia-driven immunosuppressive mechanisms.

Engineering hypoxia-fighting polymeric cryogels to boost antitumor T cells

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.