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Hypoxia is a typical characteristic of most solid malignancies, which has multiple effects on malignant phenotypes and biological behaviors of tumors including epithelial-mesenchymal-transition (EMT), invasion, migration, metastasis, autophagy, stem cell maintenance, pathological angiogenesis, drug resistance, and immunosuppression. Rcentlyumoand reversing the tumor hypoxic environment via nanotechnology has emerged as a novel therapeutic approach for the treatment of malignancies. The main strategies related to nanotechnology to alleviate or ameliorate hypoxic environment are as follows: (1) Bringing external oxygen to tumor hypoxic microenvironment; (2) Generating oxygen based on nanotechnology in situ; (3) Regulating the structure of the tumor microenvironment; (4) Decreasing oxygen consumption in the tumor microenvironment. In this review, we will discuss these nanotechnologies in detail.

BackgroundSolid tumors pose unique roadblocks to treatment with chimeric antigen receptor (CAR) T cells, including limited T-cell persistence, inefficient tumor infiltration, and an immunosuppressive tumor microenvironment. To date, attempts to overcome these roadblocks have been unsatisfactory. Herein, we reported a strategy of combiningRunx3(encoding RUNX family transcription factor 3)-overexpression with ex vivo protein kinase B (AKT) inhibition to generate CAR-T cells with both central memory and tissue-resident memory characteristics to overcome these roadblocks.MethodsWe generated second-generation murine CAR-T cells expressing a CAR against human carbonic anhydrase 9 together withRunx3-overexpression and expanded them in the presence of AKTi-1/2, a selective and reversible inhibitor of AKT1/AKT2. We explored the influence of AKT inhibition (AKTi),Runx3-overexpression, and their combination on CAR-T cell phenotypes using flow cytometry, transcriptome profiling, and mass cytometry. The persistence, tumor-infiltration, and antitumor efficacy of CAR-T cells were evaluated in subcutaneous pancreatic ductal adenocarcinoma (PDAC) tumor models.ResultsAKTi generated a CD62L+central memory-like CAR-T cell population with enhanced persistence, but promotable cytotoxic potential.Runx3-overexpression cooperated with AKTi to generate CAR-T cells with both central memory and tissue-resident memory characteristics.Runx3-overexpression enhanced the potential of CD4+CAR T cells and cooperated with AKTi to inhibit the terminal differentiation of CD8+CAR T cells induced by tonic signaling. While AKTi promoted CAR-T cell central memory phenotype with prominently enhanced expansion ability,Runx3-overexpression promoted the CAR-T cell tissue-resident memory phenotype and further enhanced persistence, effector function, and tumor-residency. These novel AKTi-generatedRunx3-overexpressing CAR-T cells exhibited robust antitumor activity and responded well to programmed cell death 1 blockade in subcutaneous PDAC tumor models.ConclusionsRunx3-overexpression cooperated with ex vivo AKTi to generate CAR-T cells with both tissue-resident and central memory characteristics, which equipped CAR-T cells with better persistence, cytotoxic potential, and tumor-residency ability to overcome roadblocks in the treatment of solid tumors.

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