Oxidative Stress-Inducing Anticancer Therapies: Taking a Closer Look at Their Immunomodulating Effects

Abstract

Cancer cells are characterized by higher levels of reactive oxygen species (ROS) compared to normal cells as a result of an imbalance between oxidants and antioxidants. However, cancer cells maintain their redox balance due to their high antioxidant capacity. Recently, a high level of oxidative stress is considered a novel target for anticancer therapy. This can be induced by increasing exogenous ROS and/or inhibiting the endogenous protective antioxidant system. Additionally, the immune system has been shown to be a significant ally in the fight against cancer. Since ROS levels are important to modulate the antitumor immune response, it is essential to consider the effects of oxidative stress-inducing treatments on this response. In this review, we provide an overview of the mechanistic cellular responses of cancer cells towards exogenous and endogenous ROS-inducing treatments, as well as the indirect and direct antitumoral immune effects, which can be both immunostimulatory and/or immunosuppressive. For future perspectives, there is a clear need for comprehensive investigations of different oxidative stress-inducing treatment strategies and their specific immunomodulating effects, since the effects cannot be generalized over different treatment modalities. It is essential to elucidate all these underlying immune effects to make oxidative stress-inducing treatments effective anticancer therapy.

Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

“…The crosstalk between inflammatory and oxidative stress mediators may form a positive feed-back loop termed “oxinflammation”, shaping the outcome of antitumor immune responses [ 68 ]. ROS in the TME, along with other mechanisms, are used by cancer cells and immunosuppressive cells to create immune tolerance to tumors [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. Here, we focus on the impact of ROS on several types of immune cells with relevance to cancer immunotherapy.…”

Plasma-Activated Medium Potentiates the Immunogenicity of Tumor Cell Lysates for Dendritic Cell-Based Cancer Vaccines

“…However, 25% of PAM reduced LPS/IFN-γ-induced increase in IL-10 production by these cells. Unlike T and NK cells, which are more susceptible to ROS-inducing treatments [ 76 , 77 ], monocytes and DCs are more resistant due to their stronger anti-oxidative protection systems allowing them to secrete ROS as a part of normal immune functions [ 12 , 20 , 78 ]. However, an increased presence of exogenous ROS or their prolonged presence could induce depletion of glutathione in DCs leading to their reduced maturation and Th1 polarization capacity [ 79 ].…”

“…The first includes a direct cytotoxic effect caused by RONS- mediated intracellular oxidative stress followed by inactivation by anti-oxidative mechanisms. This phenomenon is of special relevance, knowing that the increase of pro-oxidative mechanisms in the tumor could be beneficial for tumor therapy [ 12 ]. The second pathway involves activation of the anti-tumor immune response by molecules released from CAP- and PAM-dependent immunogenic cell death (ICD) [ 13 ].…”

Sparstolonin B exerts beneficial effects on prostate cancer by acting on the reactive oxygen species‐mediated PI3K/AKT pathway

“…ROS can lead to DNA mutations associated with tumourigenesis, and the levels of ROS are usually elevated in tumour cells; generally, the antioxidant system of tumour cells can also be activated, to maintain stability of the redox system 50 . It is believed that this plays a positive role in tumour treatment, 51 and the accumulation of continuous high levels of ROS can induce tumour cell apoptosis. In clinical application, many FDA‐approved drugs also control the progression of tumours by increasing the level of ROS 52 .…”