Bioengineered cryogels overcome hypoxia-driven tolerance and restore antitumor immunity

Cancer immunotherapy continues to face major challenges from the oxygen (O 2 )-deprived tumor microenvironment, which suppresses dendritic cell (DC) and T cell function critical for antitumor immunity. To address this, we leveraged O 2 -cryogels, injectable hyaluronic acid-based scaffolds engineered for controlled O 2 release to counteract hypoxia-induced immunosuppression. O 2 -cryogels exhibited robust physicochemical properties, tunable O 2 delivery, and biocompatibility. Notably, they blocked the hypoxia-driven shift of DCs toward a tolerogenic phenotype, preserving an immunostimulatory profile that restored antigen uptake, migration, pro-inflammatory cytokine secretion, and the expression of activation and co-stimulatory markers essential for CD8 + T cell priming and cytotoxic responses. This immune reactivation re-established DC-T cell crosstalk, enhanced cytotoxic T cell proliferation, reduced regulatory T cell induction, and reinforced tumor cell killing under hypoxic conditions. By preventing tolerogenic immune reprogramming and restoring effective antitumor immunity, O 2 -cryogels emerge as a powerful biomaterial platform to overcome hypoxia and potentially improve cancer immunotherapies.