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Tumors with a low level of pre-existing immune cell infiltration respond poorly to immune checkpoint therapies. Oncolytic viruses optimize immunotherapies by modulating the tumor microenvironment and affecting multiple steps in the cancer-immunity cycle, making them an attractive agent for combination strategies. We engineered an HSV-1-based oncolytic virus and investigated its antitumor effects in combination with the marketed PD-1 antibody Keytruda (pembrolizumab) in hPD-1 knock-in mice bearing non-immunogenic B16-F10 melanoma. Our results showed enhanced CD8+ and CD4+ T cell infiltration, IFN-γ secretion and PD-L1 expression in tumors, subsequently leading to the prolonged overall survival of mice. Systemic changes in lymphocyte cell proportions were also observed in the peripheral blood. In summary, these findings provide evidence that oncolytic viruses can be engineered as a potential platform for combination therapies, especially to treat tumors that are poorly responsive to immune checkpoint therapy. 1 An oncolytic virus VT09X optimizes the anti-PD-1 antibody therapy in low immunogenic melanoma. 2 Humanized PD-1 knock-in mice were used for in vivo study against melanoma. 3 Stimulation of TIL in local tumors and peripheral blood was performed. 4 Several molecule expressions relative to T cell response such as β2M and IFN-γ were evaluated. [ABSTRACT FROM AUTHOR]

[Display omitted] • The nanogel DOX@Mn-Alg achieved synergistic chemo/chemodynamic therapy. • The DOX@Mn-Alg self-supplied H 2 O 2 via overexpression of NOX2 and NOX4. • The DOX@Mn-Alg can boost systemic antitumor immune response. As an interesting alternative to traditional cancer therapies, chemodynamic therapy (CDT) can kill cancer cells via the conversion of endogenous hydrogen peroxide (H 2 O 2) into highly toxic hydroxyl radicals (⋅OH). However, the slow release of catalyst ions and insufficient H 2 O 2 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 H 2 O 2 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 Mn2+-mediated CDT by supplying H 2 O 2 within the tumor cells. As a result, the DOX@Mn-Alg showed synergetic antitumor activity without causing distinct systemic toxicity, and also achieved T 1 -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 Mn2+-chelating nanogels with the ability to self-supply H 2 O 2 can provide additional strategy for synergetic CDT therapy and also exhibit a promising potential for cancer immunotherapy. [ABSTRACT FROM AUTHOR]