Immunological tolerance induced by the hypoxic tumor microenvironment has been a major challenge for current immune checkpoint blockade therapies. Here, a hypoxia-responsive drug delivery nanoplatform is reported to promote chemoimmunotherapy of cancer by overcoming the hypoxia-induced immunological tolerance of tumors. The nanovesicles are assembled from manganese ferrite nanoparticles (MFNs) grafted with hypoxia-responsive amphiphilic polymers as the membrane, with doxorubicin hydrochloride (Dox) loaded in the aqueous cavities. Under hypoxic conditions in tumors, the nanovesicles can rapidly dissociate into individual MFNs to release Dox and induce decomposition of tumor endogenous HO for tumor hypoxia relief. As a result, the Dox-loaded nanovesicles display remarkable suppression of primary tumor growth in combination with αPD-L1-mediated checkpoint blockade therapy. Furthermore, the modulation of the hypoxic tumor microenvironment facilitates a long-lasting immunological memory effect to prevent tumor recurrence and metastasis. Therefore, this hypoxia-responsive nanoplatform presents a potential strategy for both local tumor treatment and long-term protection against tumor recurrence.