In this study, we link hypoxic tumor microenvironment to the resistance of immunotherapy, further highlighting the importance of tumor hypoxic microenvironment in cancer therapy. Our results reveal that hypoxia is an important barrier for T cell
infiltration, thereby limiting the efficacy of immunotherapy. Improving tumor microenvironment by inhibition of tumor cell oxidative metabolism will significantly increase sensitivity to immunotherapy, unleashing antitumor immune response to promote cancer regression [20, 31, 32]. This was strongly supported by our data that both quantity and activity of the immune cells were increased after improving tumor microenvironment [33, 34]. Taken together, the situation of tumor environment directly determines the efficacy of cancer immunotherapy. Thus, tumor microenvironment has to be considered for cancer therapy, especially hypoxia environment [35, 36].
In general, two strategies “direct delivery of oxygen to tumor” and “reduce tumor oxygen consumption” are often designed to improve tumor hypoxia. However, the latter method is more advantageous for achieving with the drugs. There is evidence showing that normalizing tumor hypoxia by existing drugs is experimentally feasible for clinical treatment of cancers . In this study, our data strongly indicated that atovaquone, an FDA-approved drug for malaria treatment, significantly alleviated the harsh hypoxic tumor microenvironment. Although other drugs can also achieve similar effects by inhibiting tumor oxygen consumption, atovaquone exhibits the most powerful effect on lowering tumor oxygen consumption. More importantly, it does not exert toxic effects for major organs at an adequate dose to improve hypoxia . However, the extremely low water-solubility of atovaquone leads to its poor bioavailability, thereby greatly limiting its clinical utility. It is very necessary to improve its bioavailability in order to meet clinical needs. Thus, designing a proper delivery system will be an effective strategy to address the above mentioned dilemma.
Albumin has good biocompatibility and biodegradability, thus serving as a versatile carrier for drug delivery . One of the best known examples is albumin-bound paclitaxel (nab-PTX), which has been used in clinic for years . Paclitaxel is enwrapped into albumin to form stable nanoparticles with a suitable size in order to enhance the bioavailability of PTX . Considering that atovaquone is as hydrophobic as PTX, this kind of nanoparticle will provide an effective strategy to solve delivery problem of atovaquone . Not surprisingly, our data showed that the albumin delivery system was able to load atovaquone, which formed nanoparticles named HSA-ATO NPs. Compared to traditional oral drug administration, the dose of HSA-ATO NPs to normalize tumor hypoxia was drastically reduced by as much as 10-fold. Under the premise of the same curative effect, this kind of nano-drugs greatly reduces the dose of atovaquone for clinical treatment. Moreover, due to the EPR effect and specific albumin receptors in malignant tumors, HSA-ATO NPs possessed the excellent targeting efficiency to tumor [24, 27, 40]. This also verified that albumin delivery system increased the bioavailability of the loaded drugs and maintained a highly biocompatible profile.
It is the fact that clinical tumors are highly heterogeneous in terms of tumor microenvironment containing endothelial cells, pericytes, immune cells, fibroblasts and extracellular matrix (ECM) [41–43]. The xenograft tumor model derived from a single cell line can not fully reflect complete tumor microenvironment, while PDX model will effectively mimic the native tumor microenvironment [44, 45]. In this study, our data demonstrated that the HSA-ATO NPs effectively alleviated tumor hypoxia in PDX mouse model, indicating that this kind of nano-drug has a great potential for the treatment of cancer patients. Importantly, all raw materials used in this study are FDA-approved, thus HSA-ATO NPs are all considered as safe and reliable in clinic. Based on this system, a number of improvements also could be made. One of them is that make the checkpoint antibodies directly conjugate to albumin by unique chemical modifications. As a consequence, this will form a more complex nano-drugs to solve a variety of problems, such as the drugs with low bioavailability or poor tumor targeting. In the near future, we may carry out other combined treatment regimens by this safe and targeting delivery system. Thus, we are going to persist exploiting this system to investigate more issues.