Hypoxia-modulatory nanomaterials to relieve tumor hypoxic microenvironment and enhance immunotherapy: Where do we stand?

Abstract The past several years have witnessed the blooming of emerging immunotherapy, as well as their therapeutic potential in remodeling the immune system. Nevertheless, with the development of biological mechanisms in oncology, it has been demonstrated that hypoxic tumor microenvironment (TME) seriously impairs the therapeutic outcomes of immunotherapy. Hypoxia, caused by Warburg effect and insufficient oxygen delivery, has been considered as a primary construction element of TME and drawn tremendous attention in cancer therapy. Multiple hypoxia-modulatory theranostic agents have been facing many obstacles and challenges while offering initial therapeutic effect. Inspired by versatile nanomaterials, great efforts have been devoted to design hypoxia-based nanoplatforms to preserve drug activity, reduce systemic toxicity, provide adequate oxygenation, and eventually ameliorate hypoxic-tumor management. Besides these, recently, some curative and innovative hypoxia-related nanoplatforms have been applied in synergistic immunotherapy, especially in combination with immune checkpoint blockade (ICB), immunomodulatory therapeutics, cancer vaccine therapy and immunogenic cell death (ICD) effect. Herein, the paramount impact of hypoxia on tumor immune escape was initially described and discussed, followed by a comprehensive overview on the design tactics of multimodal nanoplatforms based on hypoxia-enabled theranostic agents. A variety of nanocarriers for relieving tumor hypoxic microenvironment were also summarized. On this basis, we presented the latest progress in the use of hypoxia-modulatory nanomaterials for synergistic immunotherapy and highlighted current challenges and plausible promises in this area in the near future. Statement of Significance : Cancer immunotherapy, emerging as a novel treatment to eradicate malignant tumors, has achieved a measure of success in clinical popularity and transition. However, over the last decades, hypoxia-induced tumor immune escape has attracted enormous attention in cancer treatment. Limitations of free targeting agents have paved the path for the development of multiple nanomaterials with the hope of boosting immunotherapy. In this review, the innovative design tactics and multifunctional nanocarriers for hypoxia alleviation are summarized, and the smart nanomaterial-assisted hypoxia-modulatory therapeutics for synergistic immunotherapy and versatile biomedical applications are especially highlighted. In addition, the challenges and prospects of clinical transformation are further discussed.