Fatty acid metabolism and radiation-induced anti-tumor immunity

The unprecedented bench-to-bedside success of modern immunotherapies has transformed the standard of care for various advanced malignancies. To date, several monoclonal antibodies that target inhibitory receptors of T cells; namely, programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA4); have been approved by the FDA for the treatment of numerous cancers including melanoma, non-small cell lung cancer, renal cancer, lymphoma, and mismatch repair-deficient colon cancer (Twomey and Zhang, 2021). These positive outcomes have highlighted the fact that in a minority of patients, the immune system is capable to recognize and eliminate cancer cells if sufficient co-stimulatory signals are administered.

However, clinical experience with immunotherapy also informed that most tumors exhibit high degree of primary or acquired resistance that prevent clinical benefit for the majority of patients (Sharma et al., 2017). Monitoring of immune responses uncovered the tumor microenvironment (TME) as a major barrier to anti-tumor immunity with tumor cell intrinsic and extrinsic factors that promote immunosuppression (Sharma et al., 2017). While host resistance mechanisms to immunotherapy are under active investigations, how cancer cells initiate the development of immunosuppression in the TME is not completely understood.

Metabolic reprograming of the TME has emerged as an underexplored mechanism of immunoregulation essential for immune evasion (DePeaux and Delgoffe, 2021; Li et al., 2019; Zhao et al., 2021). Although angiogenesis is increased in the TME, the demand of glucose and oxygen required for cell proliferation and function is not met, thus cancer and immune cells must adapt to the metabolic cues and use alternative energy sources to survive. Recently, the effects of fatty acids (FAs) metabolism on tumorigenesis and immune escape have generated a lot of attention (Koundouros and Poulogiannis, 2020). Not only FAs can be utilized as an alternative source to cope for the energy demand, but they are critical building blocks for the structure, fluidity, and function of the cellular membrane. Consequently, elevated FAs uptake and de novo FAs synthesis in neoplastic cells is a common feature in several cancers (Eltayeb et al., 2022; Marino et al., 2020; Taib et al., 2019). Ultimately, this increase of FAs avidity results in aberrant FAs accumulation in cancer cells and in the TME. The effects of FAs metabolism reprogramming in shaping anti-tumor immunity remains elusive. In fact, the diversity and complex composition of FAs can elicit opposite responses in a given immune cell type. For instance, FAs can block tumor cell kill by cytotoxic T lymphocytes (Kleinfeld and Okada, 2005; Richieri and Kleinfeld, 1990) while they are required to fuel memory of CD8+ T cells (Howie et al., 2017a; O'Sullivan et al., 2014; Raud et al., 2018). Therefore, depending on the content and type of FAs available in the TME, FA metabolism can promote anti-tumor immunity or immune evasion.

Targeting FA metabolism to improve responses of immune checkpoint blockers is currently under active investigations. A detailed discussion summarizing such can be found here (Wang et al., 2022).

Oxidative stress occurs because of an excess level of reactive oxygen species (ROS) and/or a dysfunctional antioxidant system (Gorrini et al., 2013). Radiation therapy (RT), a standard-of-care for most cancers, induces excessive ROS accumulation which is detrimental to cellular homeostasis (Liu et al., 2022).

To decrease ROS toxicity and maintain cell survival, irradiated cancer cells reprogram their metabolism to trigger a cytoprotective response to oxidative stress by increasing FA metabolism to generate lipid droplets (LDs) (Bensaad et al., 2014; Jin et al., 2018; Nistico et al., 2021). As FA metabolism reprogramming is emerging as a critical immune regulator, elucidating its impact in irradiated tumors is essential to implement innovative approaches that will both exploit cytocidal and immunogenic properties of RT to generate long-lasting anti-tumor immunity against cancer (De Martino et al., 2021).

In this review, we critically discuss the complex network of FAs metabolism and how it influences immune response especially in the context of RT.

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