As an interesting alternative to traditional cancer therapies, chemodynamic therapy (CDT) can kill cancer cells via the conversion of endogenous hydrogen peroxide (HO) into highly toxic hydroxyl radicals (⋅OH). However, the slow release of catalyst ions and insufficient HO levels severely limit the performance of CDT. To address these issues, we explored the doxorubicin (DOX)-loaded manganese-alginate nanogel DOX@Mn-Alg with self-supplying HO capability by using a microfluidic chip. After internalization into tumor cells, DOX@Mn-Alg quickly releases DOX in a pH-responsive manner. The released DOX can not only kill tumor cells directly but also improve Mn-mediated CDT by supplying HO within the tumor cells. As a result, the DOX@Mn-Alg showed synergetic antitumor activity without causing distinct systemic toxicity, and also achieved T-weighted magnetic resonance imaging (MRI) enhancement for cancer diagnosis. Moreover, DOX@Mn-Alg treatment can promote DC maturation and increase tumor infiltration of CD8 T cells. It is believed that these Mn-chelating nanogels with the ability to self-supply HO can provide additional strategy for synergetic CDT therapy and also exhibit a promising potential for cancer immunotherapy.