Nanovaccines; Tumor immune microenvironment; Tumor-associated macrophagesNanovacunes; Microambient immune tumoral; Macròfags associats al tumorNanovacunas; Microambiente inmune tumoral; Macrófagos asociados al tumorImmune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co-delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)-β expression using a polyoxazoline (POx)-poly(lactic-co-glycolic) acid (PLGA) nanovaccine, while modulating the tumor-associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti-programmed cell death protein 1 (PD-1) can constitute an alternative approach for cancer immunotherapy. POx-Mannose (Man) nanovaccines generate antigen-specific T-cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)-Man nanovaccines. This anti-tumor effect induced by the POx-Man nanovaccines is mediated by a CD8+-T cell-dependent mechanism, in contrast to the PEG-Man nanovaccines. POx-Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD-1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti-tumor effect induced by the combination of nanovaccines with the inhibition of both TAM- and PD-1-inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.Funding: R.S.-F. and H.F.F. thank the following funding agencies for their generous support: The project that gave rise to these results has received funding from the “la Caixa” Foundation under the grant agreements LCF/PR/HR22/52420016, LCF/PR/HR19/52160021, and LCF/TR/CD20/52700005 (R.S.-F. and H.F.F). H.F.F thanks the generous financial support from The Fundação para a Ciência e Tecnologia-Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) (EXPL/MED-QUI/1316/2021, PTDC/BTM-SAL/4350/2021, UTAP-EXPL/NPN/0041/2021, UIDB/04138/2020, UIDP/04138/2020). R.S.-F. thanks to the European Research Council (ERC) PoC Grant Agreement no. 101113390 and ERC Advanced Grant Agreement no. 835227, the Israel Science Foundation (1969/18), the Melanoma Research Alliance (Established Investigator Award no. 615808 to R.S.-F.), the Israel Cancer Research Fund (ICRF) Professorship award (no. PROF-18-682), the Morris Kahn Foundation. B.C. is supported by the FCT-MCTES (Ph.D. Fellowship SFRH/BD/131969/2017). The authors also acknowledge the NIH Tetramer Core Facility for the provision of Adpgk tetramers, in addition to the Comparative Pathology Unit of IMM and the Histopathology Facility of IGC for supporting the histopathological study
