Molecularly tailoring an oxygen-carrying binary nanomodulator for integrated hypoxia/immunosuppression relief and hypersensitive immunogenic chemotherapy of triple-negative breast cancer

• Hypoxia/immunosuppression dominates the resistance to immunogenic chemotherapy of TNBC. • Molecularly tailoring strategy avoids the off-target toxicity of DOX to immune cell populations. • The carrier-free nanomodulator exhibits outstanding oxygen carrying efficiency (≈80 mg L −1 ). • The binary oxygen-carrying nanomodulator conquers hypoxia-related immune resistance. • The nanomodulator enables hypersensitive chemo-immunotherapy and tumor metastasis prevention. The regimen of combining anthracyclines with immune checkpoint inhibitors (ICIs) has been recommended for the treatment of triple-negative breast cancer (TNBC), but the clinical outcomes fall short of estimates. Our analysis of clinical patient samples reveals that this is highly correlated with hypoxia-related immune resistance. To achieve an integrated immunosuppression relief, we elaborately exploit an oxygen-carrying nanomodulator co-assembled by a redox-responsive fluorinated prodrug (DSSF) of doxorubicin (DOX) and a PD-L1 inhibitor (JQ1). The fluorinated DOX prodrug not only confers stable co-assembly with JQ1, but also endows the nanomodulator with outstanding oxygen-carrying capacity (∼80 mg L −1 ). Moreover, redox-responsive prodrug activation in tumor cells triggers synchronous release of JQ1 to downregulate the PD-L1 on tumor cells. As expected, the nanomodulator significantly alleviates hypoxia and relieves immunosuppression, displaying striking effects in immunogenic chemotherapy, tumor recurrence and metastasis prevention against TNBC. This study offers a facile and feasible solution to potentiate chemo-immunotherapy of TNBC.