In addition to being a major source of energy, mitochondria play crucial roles in various cellular functions. These include providing precursors for generating structural and functional components and coordinating with the endoplasmic reticulum (ER) to maintain calcium ion (Ca+2) homeostasis within cells (Duchen, 2000, Spinelli and Haigis, 2018, Tanwar et al., 2021). Mitochondria regulate the intrinsic apoptotic pathway, responding to signals of damage and stress. Furthermore, mitochondria are central in both the innate sensing of cellular stress and in producing damage-associated molecular patterns (DAMPs). When cells encounter stressors like disrupted Ca+2 balance, reactive oxygen species (ROS), pathogenic threats, or the compromised integrity of mitochondrial membranes, the structural components of the membrane are either oxidized or released into the cytosol where they become detectable by cytosolic or cell surface receptors associated with innate and inflammatory responses (Brookes et al., 2004, Murakami et al., 2012, Zhao et al., 2020).

During the early stages of cellular transformation, the host immune system actively removes precancerous or transformed cells. This initial elimination phase is succeeded by the establishment of quiescent tumors in an equilibrium state, where tumor growth is held in check by potent antitumor forces. However, prolonged inflammation within the tumor microenvironment and the manipulation of the immune response by the tumor cells can lead to diminishing antitumor immune functions (Maiorino et al., 2022, Mittal et al., 2014). Critical in shaping this subdued tumor microenvironment are mitochondrial DAMPs including Adenosine triphosphate (ATP), mitochondrial DNA (mtDNA), and mitochondrial RNA (mtRNA). These molecules trigger multiple innate inflammatory signaling pathways such as NFκB and IRF-3/7, leading to the release of pro-inflammatory cytokines and chemokines. When these inflammatory signals persist in the tumor microenvironment they can drive the infiltration of immunosuppressive immune cells like myeloid-derived suppressor cells (MDSCs) into the tumor milieu (Riley and Tait, 2020, Zhang et al., 2022).

The production of mitochondrial reactive oxygen species (mtROS) can inflict DNA damage, leading to the accumulation of genetic instabilities and mutations that promote immune tolerance within tumor cells. Mutations occurring within antigen processing pathways have been identified as drivers of immune tolerance and evasion. Furthermore, the instability of nuclear and mitochondrial genomes due to mtROS-induced damage can result in the release of double-stranded DNA (dsDNA) into the cytosol. Both mtDNA and cytosolic DNA in the cytosol are detected by the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, triggering the release of interferons via interferon regulatory factors (IRFs) (Marchi et al., 2022, Orekhov et al., 2022, Zhang et al., 2022). While interferon signaling initially stimulates antitumor functions within the tumor microenvironment, it can also lead to elevated levels of immune checkpoint molecules like PD-L1. These factors may further contribute to immune anergy and resistance to immunotherapies.

While the link between inflammation and tumorigenesis is poorly understood, there have been multiple studies which state that prolonged inflammation increases the likelihood of mutations and chromatin instability. Additionally, chronic inflammation, via the mitochondrial DAMPs sensing, promotes cancer invasion and metastasis. There is a multitude of clinical evidence linking chronic inflammation to poor prognosis in various cancers including colon cancer, prostate cancer, and liver cancer. This article discusses the innate sensing of the mitochondrial components which may contribute to chronic inflammation, cancer growth, and resistance to therapy.