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. 2022 Feb 19;41:68. doi: 10.1186/s13046-022-02272-x

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 8 — A Schematic representation of mechanism by which NanoMnSor can serve as theranostic anticancer agent. Oxygen generated from NanoMnSor alleviates tumor hypoxia and modulates TME. (1) NanoMnSor treatment overcomes hypoxia-driven resistance to sorafenib and reduces cell proliferation in HCC. (2) NanoMnSor ameliorates immunosuppressive TME by reducing hypoxia-induced tumor infiltration of TAMs, promoting macrophage polarization toward immunostimulatory M1, increasing CD8+ cells, leading to improving efficacy of anti-PD-1 and whole-cell cancer vaccine. (3) NanoMnSor suppresses metastasis in HCC by attenuating hypoxia induced EMT. (4) NanoMnSor treatment enhances antiangiogenic effect of sorafenib via hypoxia alleviation. (5) NanoMnSor potentially serves as CA for tumor imaging because of acidic and redox-active TME-induced decomposition of MnO2 core into Mn2+ ions that enhances tumor contrast in T1-weighted MRI. (B-J) NanoMnSor ameliorates immunosuppression in TME and exerts synergistic anticancer effects when combined with immunotherapy in orthotopic HCC models. B Quantification of mean vessel density in tumors, determined by CD31 and quantitated as percentage of total tumor area at right (n = 6–9). CD31-positive ECs were stained red (C) Hypoxic tumor areas in orthotopic HCA-1 tumor models after different treatments (n = 5–7) are indicated by PIMO-positive staining (green). D Treatment with NanoMnSor decreased CD45+ F4/80+ TAMs in tumors (E) BMDMs were cultured under normoxic conditions for 24 h with or without NanoMn. Quantitative measures of hydroxyl radicals generated by macrophages after exposure to NanoMn at different doses, (n = 3–6). F NanoMn increased expression of M1-like genes and decreased M2- like genes in BMDMs (G) Treatment of NanoMn and NanoMnSor primed macrophages exhibit M1-like phenotype (n = 8–10) and increased cytotoxic CD8+ T cells (H) in tumors, as measured by flow cytometry (n = 9–17). I Increased apoptosis in tumors, indicated by TUNEL staining (green) at 24 days after NanoMnSor treatment. J Sizes of orthotopic HCA-1 tumors [156]