Exploiting the tumor immune microenvironment and immunometabolism using mitochondria‐targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research

Abstract

Black and Hispanic cancer patients have a higher incidence of cancer mortality. Many factors (e.g., socioeconomic differences, insufficient access to healthcare) contribute to racial disparity. Emerging research implicates biological disparity in cancer outcomes. Studies show distinct differences in the tumor immune microenvironment (TIME) in Black cancer patients. Studies also have linked altered mitochondrial metabolism to changes in immune cell activation in TIME. Recent publications revealed a novel immunomodulatory role for triphenylphosphonium‐based mitochondrial‐targeted drugs (MTDs). These are synthetically modified, naturally occurring molecules (e.g., honokiol, magnolol, metformin) or FDA‐approved small molecule drugs (e.g., atovaquone, hydroxyurea). Modifications involve conjugating the parent molecule via an alkyl linker chain to a triphenylphosphonium moiety. These modified molecules (e.g., Mito‐honokiol, Mito‐magnolol, Mito‐metformin, Mito‐atovaquone, Mito‐hydroxyurea) accumulate in tumor cell mitochondria more effectively than in normal cells and inhibit mitochondrial respiration, induce reactive oxygen species, activate AMPK and redox transcription factors, and inhibit cancer cell proliferation. Besides these intrinsic effects of MTDs in redox signaling and proliferation in tumors, MTDs induced extrinsic effects in the TIME of mouse xenografts. MTD treatment inhibited tumor‐suppressive immune cells, myeloid‐derived suppressor cells, and regulatory T cells, and activated T cells and antitumor immune effects. One key biological disparity in Black cancer patients was related to altered mitochondrial oxidative metabolism; MTDs targeting vulnerabilities in tumor cells and the TIME may help us understand this biological disparity. Clinical trials should include an appropriate number of Black and Hispanic cancer patients and should validate the intratumoral, antihypoxic effects of MTDs with imaging.

Atovaquone enhances antitumor efficacy of TCR-T therapy by augmentation of ROS-induced ferroptosis in hepatocellular carcinoma

“…Studies have shown that ATO can also inhibit cancer cell viability by targeting the mitochondrial complex III [ 19 , 22 ], which increases the ROS levels within cancer cells. In addition, it has been reported that ATO can increase oxidative stress in vitro [ 24 ] and reduce hypoxia in vivo [ 19 ], which may enhance T cell-based cancer immunotherapy by alleviating the hypoxic conditions within the tumor microenvironment [ 50 ]. As we know, ferroptosis is a ROS-dependent form of cell death, ROS-inducing drugs (such as doxorubicin, gemcitabine, paclitaxel, 5-fluorouracil, bortezomib, and arsenic trioxide) in combination with Cyst(e)inase is considered to be new therapeutic opportunities for ferroptosis-based anticancer therapy [ 51 ].…”

Patients with Lung Cancer of Different Racial Backgrounds Harbor Distinct Immune Cell Profiles

“…Nazha and colleagues (39) addressed the underrepresentation of minority ethnic groups in clinical trials and showed that AAs represent less than 4% of all patients enrolled. Kalyanaraman and colleagues (40) proposed that altered mitochondrial oxidative metabolism and differences in the tumor immune microenvironment are critical determinants of poor clinical outcomes among AA patients. Finally, Kakarla and colleagues (41) summarized the impact of racial disparities for different cancer types (prostate, breast, ovarian and uterine, digestive, urinary, and respiratory) and concluded that aggressive forms of disease and overall mortality are higher in AAs compared with other races.…”

Polyphenolic Boronates Inhibit Tumor Cell Proliferation: Potential Mitigators of Oxidants in the Tumor Microenvironment

“…Recent publications suggest that race and ethnicity are factors that affect mitochondrial metabolism in cancer cells, and that mitochondrial metabolism in white cancer patients is considerably different than in patients from other racial and ethnic groups [67][68][69][70]. Studies have revealed distinct differences in the TME in Black cancer patients.…”