Resistance of breast cancers to chemotherapy remains a global challenge to date. Drug combination studies between anti-cancer agents are increasingly becoming therapeutic strategies, geared towards alleviating breast cancers. Previously, 2-deoxyglucose has been shown to target and interrupt glycolysis. Available evidence also suggests that diclofenac, which was originally designed as a pain reliever, could inhibit the proliferation of breast cancer cells. However, the reverse Warburg effect and other metabolic reprogramming mechanisms in breast cancers limit the pharmacological application of both 2-deoxyglucose and diclofenac as mono-therapeutic agents. The present study explores the additive anti-cancer effects of 2-deoxyglucose and diclofenac sodium on breast cancer cells. In this study, MDA-231 and MCF7 cells were treated with 2-deoxyglucose and diclofenac sodium in single and combination doses before being evaluated for viability, cell growth, reactive oxygen species, apoptotic and necrotic phases, and migration abilities. Additionally, immunoblotting of pro-apoptotic proteins, Caspase-3 and Caspase-9, and a hypoxia-inducible factor-1 alpha, was also performed. The results showed that combination treatments of the cells with the drugs exhibited additive anti-cancer effects by limiting proliferation, enhancing cytotoxic reactive oxygen species generation, enhancing apoptosis and necrosis, limiting colony formation and expansion of cells, and inhibiting cell migration. The degrees of cytotoxicity of combined treatments were almost similar in both cell lines, although with minimal differences. Put together, these results reveal the novel synergistic effects of 2-deoxyglucose and diclofenac sodium on breast cancer cells, hence potentially elevating their pharmacological profile in the overall breast cancer therapy.

The proliferation of bladder cancer (BC) cells is driven by metabolic reprogramming, marked by a glycolytic dependency to sustain uncontrolled growth. While Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) is known to promote BC progression and correlate with poor prognosis, the mechanisms underlying its upregulation and role in aerobic glycolysis remain unclear. Here, we identify E2F3 as a direct transcriptional activator of TACC3, with its amplification in BC driving elevated TACC3 expression. TACC3 overexpression enhances glycolysis, increasing glucose consumption, lactate production, and expression of glycolytic enzymes (e.g., GLUT1, HK2, PFKFB3), while its knockdown suppresses these effects. Pharmacological inhibition of glycolysis abrogates TACC3-driven tumor growth in vitro and in vivo. Mechanistically, TACC3 interacts with c-Myc, promoting its acetylation at lysine 323 (K323) by recruiting the acetyltransferase PCAF and antagonizing the deacetylase SIRT1. This acetylation stabilizes c-Myc, amplifying its transcriptional activation of glycolytic targets. Our findings establish TACC3 as a critical regulator of c-Myc-driven metabolic reprogramming in BC, highlighting its potential as a therapeutic target to disrupt glycolysis and oncogenic c-Myc signaling.

Bezafibrate (BEZ) is a drug used to treat hypertriglyceridemia and its long-term use has been associated with reduced risk of cancer in patients with coronary artery disease. Recent studies uncovered that BEZ is a potent modulator of mitochondrial biogenesis through activation of PGC-1α/PPAR complexes, resulting in modulation of lipid metabolism and fatty acid oxidation. Mitochondria impact virtually all processes linked to oncogenesis, and disruption of normal mitochondrial bioenergetics and oxidative phosphorylation (OXPHOS) occurs early during oncogenesis to change the energy metabolism of cancer cells as well as various cells in the tumor microenvironment (TME). Therefore, we synthesized a BEZ analog (Mito-BEZ) that preferentially localizes to mitochondria, thereby enabling lower doses of Mito-BEZ than BEZ to achieve greater efficacy. Our studies demonstrate that Mito-BEZ is significantly more potent than BEZ at inhibiting LUAD cell growth in vitro and inhibiting lung tumorigenesis in preclinical mouse models. Mito-BEZ was also >200-fold more potent than BEZ at inhibiting both complex I and III in LUAD cells. Furthermore, Mito-BEZ suppresses oxidative metabolism in cancer cells while markedly upregulating mitochondrial function in effector CD8+ T cells, resulting in activation of a potent T cell immune response in the TME. Our results show that Mito-BEZ, with its favorable toxicity profile, exhibited a striking inhibitory effect on lung cancer progression and metastasis by targeting a fundamental difference in metabolic plasticity between cancer cells and effector T cells in the TME.

Peroxynitrite (ONOO-), a biological oxidizing and nitrating species responsible for post-translational modification of cellular proteins, has been implicated in numerous pathologies carrying an inflammatory component. Specific detection of ONOO- in biological systems remains a challenge, and boronates are regarded as the most promising class of probes for the detection and quantitation of ONOO-. Oxidation of boronate probes by ONOO- results in the formation of minor ONOO--specific products via a pathway involving a phenyl radical-type intermediate, in addition to the major phenolic product. Here, we report fluorogenic cyclization of the phenyl-type radical formed during oxidation of a boronate probe by ONOO-, with the production of a fluorescent product, and we propose a new approach for the specific detection of ONOO- based on this observation. We characterized the kinetics and stoichiometry of the reaction of benzophenone-2-boronic acid with ONOO- and identified 2-hydroxybenzophenone as the major product and fluorenone (FLN) and 2-nitrobenzophenone as the minor ONOO--specific products. Hydrogen peroxide neither alone nor in the presence of myeloperoxidase and nitrite produces FLN or 2-nitrobenzophenone. FLN can be selectively detected using fluorescence spectroscopy, providing a chemical principle for the development of next-generation probes for ONOO-, with noninvasive, fluorescence-based detection of ONOO--specific products. Fluorescence-based monitoring of FLN was successfully applied for the detection of ONOO- generated in situ from the decomposition of SIN-1, a thermal source of the superoxide radical anion and nitric oxide.

Bidirectional amplification of oxidative stress within the mitochondria is essential to enhance photodynamic therapy (PDT), and efficient co-delivery of reducing agents and reactive oxygen species (ROS)-generating agents is critical for achieving this with minimal side effects. However, the absence of an effective platform for mitochondria-targeted co-delivery and spatially controlled tumor-specific therapy limits the potential applicability of this strategy. In this study, we developed an ROS-sensitive organosilica nanocarrier, encapsulating nanogold and introducing chlorin e6 (Ce6) and triphenylphosphine (TPP) through a one-pot sol-gel process. Following TPP-mediated mitochondria-targeted delivery, ROS generated by Ce6 under near-infrared (NIR) irradiation not only damaged the mitochondria but also disrupted the nanoparticles within the tumor, leading to the release of nanogold. These ultra-small nanogolds, due to their high surface area, exhibited enhanced glutathione scavenging capacity, which, in combination with ROS, synergistically amplified oxidative stress to overcome the high resistance of tumor cells. Both in vitro and in vivo experiments confirmed the effectiveness of this strategy, demonstrating efficient co-delivery, controlled drug release, spatially targeted oxidative stress amplification, and synergistic antitumor effects. Thus, we present a facile platform for the spatially controlled bidirectional amplification of oxidative stress with minimal side effects. STATEMENT OF SIGNIFICANCE: Mitochondrial oxidative stress involves both ROS generation and GSH depletion, indicating that bidirectional amplification is required for mitochondria-targeted antitumor therapy. However, most of existing strategies just focus on ROS generation, which limits the amplification level of oxidative stress. Thus, the mitochondria-targeted co-delivery of photodynamic agent and GSH scavenging agent is an effective approach to address this limitation. Besides, the lack of facile nanoplatform also hinders the application of strategies aimed at bidirectionally amplifying oxidative stress. In this study, we developed a facile nanoplatform for mitochondria-targeted co-delivery of the photodynamic agent Chlorin e6 and GSH scavenging agent nanogold using a ROS-responsive organosilica nanocarrier. This approach successfully achieved bidirectional amplification of oxidative stress, resulting in a synergistic antitumor effect with minimal side effects.

Dichloroacetate (DCA) has shown potential in modulating cellular metabolism and inflammation, particularly in cardiac conditions. This study investigates DCA's protective effects in a mouse model of myocardial infarction (MI), focusing on its ability to enhance cardiac function, reduce inflammation, and shift macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype.

An acute MI model was created using left anterior descending coronary artery ligation. Mice were assigned to four groups: normal control, MI control, MI + 50 mM DCA, and MI + 100 mM DCA. Cardiac fibrosis and injury were assessed through H&E staining. Cardiac function was evaluated via echocardiography, and serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were measured. Inflammation and apoptosis were analyzed through immunohistochemistry, ELISA, western blotting, and flow cytometry in heart tissue and RAW264.7 cells. Additionally, macrophage polarization and relevant signaling pathways were examined.

DCA significantly improved cardiac function in MI mice, evidenced by reduced myocardial injury and lower CK-MB and LDH levels. It also decreased inflammatory cytokines (TNF-α, IL-6 and IL-1β) and facilitated macrophage polarization from M1 to M2. Western blotting revealed that DCA inhibited iNOS and COX2 while enhancing Arg1 expression, alongside improved mitochondrial function and reduced apoptosis. Additionally, by injecting AAV-PDHK4 (pyruvate dehydrogenase kinase) into MI mice, we found that DCA effectively inhibited the progression of MI through the suppression of PDHK4.

DCA protects against myocardial infarction by enhancing cardiac function, reducing inflammation, and promoting macrophage polarization, likely through inhibition of PDHK4 and NF-κB pathways, positioning it as a potential therapeutic strategy for cardiac repair post-MI.

Breast cancer remains the most prevalent malignancy among women globally and ranks as the leading cause of cancer-related mortality in this demographic. Approximately 13 %-15 % of all breast cancer cases are classified as HER2-positive, a subtype associated with a particularly unfavorable prognosis. A large number of patients with HER2-positive breast cancer continue to face disease progression after receiving standardized treatment. Given these challenges, a thorough exploration into the mechanisms underlying drug resistance in HER2-targeted therapy is imperative. This review focuses on the factors related to drug resistance in HER2-targeted therapy, including tumor heterogeneity, antibody-binding efficacy, variations in the tumor microenvironment, and abnormalities in signal activation and transmission. Additionally, corresponding strategies to counteract these resistance mechanisms are discussed, to advance therapeutic efficacy and clinical benefits in the management of HER2-positive breast cancer.

Breast cancer (BC) ranks among the most prevalent malignancies affecting women, with advanced-stage patients facing an increased mortality risk. Myeloid-derived suppressor cells (MDSCs) contribute significantly to poor prognostic outcomes. Research has concentrated predominantly on the immunological mechanisms underlying MDSC functions, but a comprehensive investigation into the metabolic interactions between BC cells and MDSCs is lacking. In a hypoxic tumor microenvironment (TME), BC cells can enhance aerobic-glycolysis rates, upregulate expression of key lipid metabolism enzymes such as cluster of differentiation (CD) 36 and 5-lipoxygenase (5-LOX), accelerate glutamine (Gln) uptake, and elevate extracellular adenosine (eADO) levels, thereby fostering MDSC proliferation and amplifying immune suppression. Concurrently, alterations in the metabolic state of MDSCs also influence BC progression. To ensure adequate proliferative resources, MDSCs upregulate the pentose phosphate pathway and expedite glycolysis for energy supply while increasing the expression of fatty acid transport proteins (FATPs) such as CD36 and fatty acid transporter 2 (FATP2) to maintain intracellular lipid availability, thereby enhancing their adaptability within the TME. Furthermore, MDSCs undermine T-cell anti-tumor efficacy by depleting essential amino acids (AAs), such as arginine (Arg), tryptophan (Trp), and cysteine (Cys), required for T-cell function. This review elucidates how pharmacological agents such as metformin, liver X receptor (LXR) agonists, and 6-diazo-5-oxo-L-norleucine (DON) can augment anti-cancer treatment efficacy by targeting metabolic pathways in MDSCs. We systematically delineate the mechanisms governing interactions between BC cells and MDSCs from a metabolic standpoint while summarizing therapeutic strategies to modulate metabolism within MDSCs. Our review provides a framework for optimizing MDSC applications in BC immunotherapy.

Cellular metabolism plays a pivotal role in the development and progression of pancreatic ductal adenocarcinoma (PDAC), with dysregulated metabolic pathways contributing to tumorigenesis and therapeutic resistance. Distinct metabolic heterogeneity in pancreatic cancer significantly impacts patient prognosis, as variations in metabolic profiles influence tumor behavior and treatment responses.

This review explores the intricate interplay between mitochondrial dynamics, mitophagy, and cellular metabolism in PDAC. We discuss the significance of mitophagy dysregulation in PDAC pathogenesis, emphasizing its influence on treatment responses and prognosis. Furthermore, we analyze the impact of mitochondrial dynamics alterations, including fission and fusion processes, on PDAC progression and tumorigenesis.

Targeting mitochondrial metabolism holds promise for advancing PDAC therapeutics. Ongoing clinical trials underscore the therapeutic potential of modulating key regulators of mitochondrial dynamics and mitophagy. Despite inherent challenges, these approaches offer diverse strategies to enhance treatment efficacy and improve patient outcomes.

Despite available treatment approaches, including surgical resection along with chemotherapy and radiotherapy, glioblastoma (GBM), the most prevalent primary brain tumor, remains associated with a grim prognosis. Although radiotherapy is central to GBM treatment, its combination with bioenergetics regulators has not been validated in clinical practice. Here, we hypothesized that bioenergetics regulators can enhance the radio-sensitivity of GBM tumorspheres (TSs).

Gene expression profiles of GBM patient-derived TSs were obtained through microarray and RNA-seq. In vitro treatment efficacy was assessed using clonogenic assay, 3D invasion assay, neurosphere formation assay, and flow cytometry. Protein expression was measured via western blot, and γH2AX foci were detected via immunofluorescence. In vivo efficacy was confirmed in an orthotopic xenograft model.

Based on radiation response-associated gene expression, GBM TSs were classified into high- or low-radioresistant groups. Among the five bioenergetics regulators, the pentose phosphate pathway inhibitor DHEA and the glycolysis inhibitor 2-DG notably enhanced the efficacy of ionizing radiation (IR) efficacy in vitro, reducing the survival fraction, stemness, and invasiveness in high- and low-radioresistant TSs. Combination with 2-DG further stimulated IR-induced DNA damage response and apoptosis in low-radioresistant GBM TSs. RNA-seq analysis revealed a downregulation of bioenergetics- and cell cycle-associated genes, whereas extracellular matrix- and cell adhesion-associated genes were enhanced by combined IR and 2-DG treatment. This therapeutic regimen extended survival and diminished tumor size in mouse xenograft models.

Our data suggest that combination with bioenergetics regulator 2-DG enhances the radio-sensitivity of GBM TSs, highlighting the clinical potential of this combined regimen.

Peroxynitrite (ONOO‒/ONOOH) is a short-lived but highly reactive species that is formed in the diffusion-controlled reaction between nitric oxide and the superoxide radical anion. It can oxidize certain biomolecules and has been considered as a key cellular oxidant formed under various pathophysiological conditions. It is crucial to selectively detect and quantify ONOO- to determine its role in biological processes. In this review, we discuss various approaches used to detect ONOO‒ in cell-free and cellular systems with the major emphasis on small-molecule chemical probes. We review the chemical principles and mechanisms responsible for the formation of the detectable products, and plausible limitations of the probes. We recommend the use of boronate-based chemical probes for ONOO‒, as they react directly and rapidly with ONOO-, they produce minor but ONOO‒‒specific products, and the reaction kinetics and mechanism have been rigorously characterized. Specific experimental approaches and protocols for the detection of ONOO- in cell-free, cellular, and in vivo systems using boronate-based molecular probes are provided (as shown in Boxes 1-6).

Photothermal therapy (PTT) is minimally invasive, precisely controlled, and therapeutically effective treatment method. However, its efficacy is limited by the overexpression of heat shock proteins (HSP), which leads to cellular thermal blockade. Targeting mitochondria with PTT can enhance anticancer efficacy, as mitochondria encode genes related to HSP and provide energy for their production. Nevertheless, mitochondrial dynamics confer resistance to damage from external stimuli. Therefore, disrupting the balance of mitochondrial dynamics is essential to impede HSP production. Herein, we synthesized degradable Cu3BiS3 (CBS) nanosheets (NSs) with one face modified by carboxylated triphenylphosphonium (TPP) to target mitochondria. This modification increases the production of exogenous reactive oxygen species (ROS) and induces the overexpression of dynamin-related protein 1 (Drp1), disrupting mitochondrial dynamic homeostasis. The other face was modified with carboxylated β-cyclodextrin (CD) to load the glycolysis inhibitor (2-deoxyglucose, 2DG), thereby reducing adenosine triphosphate (ATP) production in the extra-mitochondrial space, as glycolysis also occurs in the cytoplasm. The resulting TPP-CBS-2DG Janus NSs (JNSs) not only disrupt mitochondrial energy production, leading to cell starvation, but also inhibit HSP production. Consequently, TPP-CBS-2DG JNSs can enhance tumor thermal sensitivity in PTT, improving its efficacy. This work holds great promise for overcoming tumor heat resistance in PTT and provides a feasible method for fabricating selectively modified multifunctional NSs.

Rapid propagation of tumor cells requires plenty of energy, which is adenosine triphosphate (ATP) dependent. ATP inhibition in tumors not only results in the starvation of tumor cells but also down-regulation of the level of heat shock proteins (HSPs), which usually increase during traditional photothermal therapy (PTT), especially when the temperature is up 50 °C. 2-deoxy-D-glucose (2DG) is an anti-glycolytic reagent and can be used as an efficient agent for ATP inhibition in tumors. Compared with typical PTT, low-temperature mild photothermal therapy (MPTT) is receiving more and more attention because it avoids the high temperatures causing damage to the normal tissue, and the increase of HSPs which decrease PTT. Here, multifunctional polypeptide nanoparticles pDG@Ahx conjugating both a NIR probe Ahx-BDP and 2DG into the side chain of the amphiphilic polypeptide have been prepared. In vitro and in vivo studies reveal that the as-prepared nanoparticles achieve a synergistic effect of starvation/MPTT/PDT (photodynamic therapy), and it provides a new strategy to NIR-I/II fluorescence imaging-guided starvation/MPTT/PDT synergy therapy for tumors.

Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/β-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.

Chemo-immunotherapy holds the advantage of specific antitumor effects by activating cytotoxic lymphocyte cells (CTLs) immune response. However, multiple barriers have limited the outcomes partly due to tumor-cell-mediated exhaustion of CTLs in the immunosuppressive tumor microenvironment (iTME). Here, we rationally designed a simple-yet-versatile Ca2+ nanogenerator to modulate iTME for enhancing 2-deoxyglucose (2-DG) mediated chemo-immunotherapy. Briefly, after 2-DG chemotherapy, CaO2 nanoparticles coated with EL4 cell membrane (denoted as CaNP@ECM) could preferentially accumulate in tumor tissue via adhesion between LFA-1 on EL4 cell membrane and ICAM-1 on inflamed endothelial cell in tumor tissues and display a series of benefits for CTLs: i) Increasing glucose availability of CTLs while reducing lactic acid secretion through Ca2+ overloading mediated inhibition of tumor cell glycolysis, as well as relieving hypoxia; ii) Reversing CTLs exhaustion via TGF-β1 scavenging and PD-L1 blockade through PD-1 and TGF-β1R on EL4 cell membrane; iii) Boosting tumor immunotherapy via immunologic death (ICD) of tumor cells induced by Ca2+ overloading. We demonstrate that the multi-modal Ca2+ nanogenerator rescues T cells from exhaustion and inhibits tumor growth both in vitro and in vivo. More importantly, the study also facilitate the development of glucose metabolism inhibition-based tumor immunotherapy via Ca2+ overloading.

Bioenergetic remodeling of core energy metabolism is essential to the initiation, survival, and progression of cancer cells through exergonic supply of adenosine triphosphate (ATP) and metabolic intermediates, as well as control of redox homeostasis. Mitochondria are evolutionarily conserved organelles that mediate cell survival by conferring energetic plasticity and adaptive potential. Mitochondrial ATP synthesis is coupled to the oxidation of a variety of substrates generated through diverse metabolic pathways. As such, inhibition of the mitochondrial bioenergetic system by restricting metabolite availability, direct inhibition of the respiratory Complexes, altering organelle structure, or coupling efficiency may restrict carcinogenic potential and cancer progression.

Here, we review the role of bioenergetics as the principal conductor of energetic functions and carcinogenesis while highlighting the therapeutic potential of targeting mitochondrial functions.

Mitochondrial bioenergetics significantly contribute to cancer initiation and survival. As a result, therapies designed to limit oxidative efficiency may reduce tumor burden and enhance the efficacy of currently available antineoplastic agents.

Depression is a common mental disorder and its pathogenesis is not fully understood. However, more and more evidence shows that mitochondrial dynamics dysfunction may play an important role in the occurrence and development of depression. Mitochondria are the centre of energy production in cells, and are also involved in important processes such as apoptosis and oxidative stress. Studies have found that there are abnormalities in mitochondrial function in patients with depression, including mitochondrial morphological changes, mitochondrial dynamics disorders, mitochondrial DNA damage, and impaired mitochondrial respiratory chain function. These abnormalities may cause excessive free radicals and oxidative stress in mitochondria, which further damage cells and affect the balance of neurotransmitters, causing or aggravating depressive symptoms. Studies have shown that mitochondrial dynamics dysfunction may participate in the occurrence and development of depression by affecting neuroplasticity, inflammation and neurotransmitters. This article reviews the effects of mitochondrial dynamics dysfunction on the pathogenesis of depression and its potential molecular pathway. The restorers for the treatment of depression by regulating the function of mitochondrial dynamics were summarized and the possibility of using mitochondrial dynamics as a biomarker of depression was discussed.

Breast cancer is the most common cancer among women worldwide, and marine creatures are the most abundant reservoir of anticancer medicines. Tachyplesin peptides have shown antibacterial capabilities, but their potential to inhibit cancer growth and trigger cancer cell death has not been investigated. A synthetic tachyplesin nucleotide sequence was generated and inserted into the pcDNA3.1( +) Mammalian Expression Vector. PCR analysis and enzyme digesting procedures were used to evaluate the vectors' accuracy. The transfection efficiency of MCF-7 and MCF10-A cells was 57% and 65%, respectively. The proliferation of MCF-7 cancer cells was markedly suppressed. Administration of plasmid DNA (pDNA) combined with tachyplesin to mice with tumors did not cause any discernible morbidity or mortality throughout treatment. The final body weight curves revealed a significant reduction in weight among mice treated with pDNA/tachyplesin and tachyplesin at a dose of 100 µg/ml (18.4 ± 0.24 gr, P < 0.05; 11.4 ± 0.24 gr P < 0.01) compared to the control group treated with PBS (22 ± 0.31 gr). Animals treated with pDNA/tachyplesin and tachyplesin exhibited a higher percentage of CD4 + Foxp3 + Tregs, CD8 + Foxp3 + Tregs, and CD4 + and CD8 + T cell populations expressing CTLA-4 in their lymph nodes and spleen compared to the PBS group. The groups that received pDNA/tachyplesin exhibited a substantial upregulation in the expression levels of caspase-3, caspase-8, BAX, PI3K, STAT3, and JAK genes. The results offer new possibilities for treating cancer by targeting malignancies using pDNA/tachyplesin and activating the mTOR and NFκB signaling pathways.

Immune cell metabolism plays a pivotal role in shaping and modulating immune responses. The metabolic state of immune cells influences their development, activation, differentiation, and overall function, impacting both innate and adaptive immunity. While glycolysis is crucial for activation and effector function of CD8 T cells, regulatory T cells mainly use oxidative phosphorylation and fatty acid oxidation, highlighting how different metabolic programs shape immune cells. Modification of cell metabolism may provide new therapeutic approaches to prevent rejection and avoid immunosuppressive toxicities. In particular, the distinct metabolic patterns of effector and suppressive cell subsets offer promising opportunities to target metabolic pathways that influence immune responses and graft outcomes. Herein, we review the main metabolic pathways used by immune cells, the techniques available to assay immune metabolism, and evidence supporting the possibility of shifting the immune response towards a tolerogenic profile by modifying energetic metabolism.

Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,2'-diol) is a biologically active natural product derived from Magnolia and has been shown to have excellent biological activities. This paper discusses research progress on the use of honokiol in the treatment of lung cancer, as studies have confirmed that honokiol can exert anti-lung-cancer effects through multiple pathways and multiple signaling pathways, such as inhibiting angiogenesis, affecting mitochondrial function and apoptosis, regulating of autophagy and epithelial-mesenchymal transition (EMT). In addition, honokiol combined with other chemotherapy drugs is also a way in which it can be applied.

The tumor microenvironment affects the structure and metabolic function of mitochondria in tumor cells. This process involves changes in metabolic activity, an increase in the amount of reactive oxygen species (ROS) in tumor cells compared to normal cells, the production of more intracellular free radicals, and the activation of oxidative pathways. From a practical perspective, it is advantageous to develop drugs that target mitochondria for the treatment of malignant tumors. Such drugs can enhance the selectivity of treatments for specific cell groups, minimize toxic effects on normal tissues, and improve combinational treatments. Mitochondrial targeting agents typically rely on small molecule medications (such as synthetic small molecules agents, active ingredients of plants, mitochondrial inhibitors or autophagy inhibitors, and others), modified mitochondrial delivery system agents (such as lipophilic cation modification or combining other molecules to form targeted mitochondrial agents), and a few mitochondrial complex inhibitors. This article will review these compounds in three main areas: oxidative phosphorylation (OXPHOS), changes in ROS levels, and endogenous oxidative and apoptotic processes.

In an effort to further investigate previously observed activity of indolyl sulfonamides towards pancreatic cancer cell lines, a library of 44 compounds has been synthesized. The biological activity of the compounds has been determined using two different screening assay techniques against 7 pancreatic cancer cell lines and 9 non-pancreatic cancer cell lines. In the first assay, the cytotoxicity of the compounds was evaluated using a traditional (48 hour compound exposure) method. An in silico investigation was conducted to determine if the compounds might be inducing cell death by inhibiting the S100A2-p53 protein-protein interaction. In the second assay, the potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (1-2 hour compound exposure) method. IC50 values of the hit compounds were obtained and four compounds displayed sub-micromolar potency against PANC-1 cells. The investigation has provided several compounds that display selective in vitro activity toward pancreatic cancer that warrant further development.

Mitochondria-targeted coenzyme Q10 (Mito-ubiquinone, Mito-quinone mesylate, or MitoQ) was shown to be an effective antimetastatic drug in patients with triple-negative breast cancer. MitoQ, sold as a nutritional supplement, prevents breast cancer recurrence. It potently inhibited tumor growth and tumor cell proliferation in preclinical xenograft models and in vitro breast cancer cells. The proposed mechanism of action involves the inhibition of reactive oxygen species by MitoQ via a redox-cycling mechanism between the oxidized form, MitoQ, and the fully reduced form, MitoQH2 (also called Mito-ubiquinol). To fully corroborate this antioxidant mechanism, we substituted the hydroquinone group (-OH) with the methoxy group (-OCH3). Unlike MitoQ, the modified form, dimethoxy MitoQ (DM-MitoQ), lacks redox-cycling between the quinone and hydroquinone forms. DM-MitoQ was not converted to MitoQ in MDA-MB-231 cells. We tested the antiproliferative effects of both MitoQ and DM-MitoQ in human breast cancer (MDA-MB-231), brain-homing cancer (MDA-MB-231BR), and glioma (U87MG) cells. Surprisingly, DM-MitoQ was slightly more potent than MitoQ (IC50 = 0.26 μM versus 0.38 μM) at inhibiting proliferation of these cells. Both MitoQ and DM-MitoQ potently inhibited mitochondrial complex I-dependent oxygen consumption (IC50 = 0.52 μM and 0.17 μM, respectively). This study also suggests that DM-MitoQ, which is a more hydrophobic analog of MitoQ (logP: 10.1 and 8.7) devoid of antioxidant function and reactive oxygen species scavenging ability, can inhibit cancer cell proliferation. We conclude that inhibition of mitochondrial oxidative phosphorylation by MitoQ is responsible for inhibition of breast cancer and glioma proliferation and metastasis. Blunting the antioxidant effect using the redox-crippled DM-MitoQ can serve as a useful negative control in corroborating the involvement of free radical-mediated processes (e.g., ferroptosis, protein oxidation/nitration) using MitoQ in other oxidative pathologies.

As the main systemic treatment for triple-negative breast cancer (TNBC), the bleak medical prognosis of chemotherapy resulted in impaired life quality by tumor recurrence and metastasis. The feasible cancer starvation therapy could inhibit tumor progression by blocking energy supplements, however, the mono-therapeutic modality showed limited curing efficacy due to heterogeneity and abnormal energy metabolism of TNBC. Thus, the development of a synergistic nano-therapeutic modality involving different anti-tumor mechanisms to simultaneously transport medicines to the organelle where metabolism took place, might remarkably improve curing efficacy, targeting ability, and bio-safety. Herein, the hybrid BLG@TPGS NPs were prepared by doping multi-path energy inhibitors Berberine (BBR) and Lonidamine (LND) as well as the chemotherapeutic agent Gambogic acid (GA). Our research indicated that Nanobomb\mathord{-} BLG@TPGS NPs inherited the mitochondria targeting ability from BBR to accumulate precisely at the "energy factory" mitochondria, and then induce starvation therapy to efficiently eradicated cancer cells by coordinately powered off tumor cells via a "three-prone strategy" to cut off mitochondrial respiration, glycolysis, and glutamine metabolism. The inhibition of tumor proliferation and migration was enlarged by the synergistic combination with chemotherapy. Besides, apoptosis via mitochondria pathway and mitochondria fragmentation supported the hypothesis that NPs eliminated MDA-MB-231 cells by violently attacking MDA-MB-231 cells and especially the mitochondria. In summary, this synergistic chemo-co-starvation nanomedicine proposed an innovative site-specific targeting strategy for improved tumor treatment and decreased toxicity to normal tissues, which provided an option for clinical TNBC-sensitive treatment.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second most deadly type of cancer worldwide. In late diagnosis, CRC can resist therapy regimens in which cancer stem cells (CSCs) are intimately related. CSCs are a subpopulation of tumor cells responsible for tumor initiation and maintenance, metastasis, and resistance to conventional treatments. In this scenario, colorectal cancer stem cells (CCSCs) are considered an important key for therapeutic failure and resistance. In its turn, mitochondria is an organelle involved in many mechanisms in cancer, including chemoresistance of cytotoxic drugs due to alterations in mitochondrial metabolism, apoptosis, dynamics, and mitophagy. Therefore, it is crucial to understand the mitochondrial role in CCSCs regarding CRC drug resistance. It has been shown that enhanced anti-apoptotic protein expression, mitophagy rate, and addiction to oxidative phosphorylation are the major strategies developed by CCSCs to avoid drug insults. Thus, new mitochondria-targeted drug approaches must be explored to mitigate CRC chemoresistance via the ablation of CCSCs.

N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. NAC is not readily bioavailable and is used in high concentrations. The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. Here, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito₁₀-NAC) that is functionally similar to NAC was synthesized and studied. Mito₁₀-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito₁₀-NAC is nearly 2000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito₁₀-NAC also inhibited cancer cell proliferation. Mito₁₀-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation. Results suggest that the antiproliferative effects of NAC and Mito₁₀-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group-dependent redox modulatory effects.

Human cytomegalovirus (HCMV) exploits host mitochondrial function to promote viral replication. HCMV gene products have been described to directly interact and alter functional or structural aspects of host mitochondria. Current antivirals against HCMV, such as ganciclovir and letermovir, are designed against viral targets. Concerns with the current antivirals include toxicity and viral resistance. Targeting host mitochondrial function is a promising alternative or complimentary antiviral approach as (1) drugs targeting host mitochondrial function interact with host targets, minimizing viral resistance, and (2) host mitochondrial metabolism plays key roles in HCMV replication. This review describes how HCMV alters mitochondrial function and highlights pharmacological targets that can be exploited for novel antiviral development.

Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.

Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most significant public health challenges of this era. To date, the scientific community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. Permeabilization of the mitochondrial membranes has been implicated as the most considerable footprint in apoptosis-mediated cancer cell death. Under the condition of mitochondrial calcium overload, exclusively mediated by oxidative stress, an opening of a nonspecific channel with a well-defined diameter in mitochondrial membrane allows free exchange between the mitochondrial matrix and the extra mitochondrial cytosol of solutes and proteins up to 1.5 kDa. Such a channel/nonspecific pore is recognized as the mitochondrial permeability transition pore (mPTP). mPTP has been established for regulating apoptosis-mediated cancer cell death. It has been evident that mPTP is critically linked with the glycolytic enzyme hexokinase II to defend cellular death and reduce cytochrome c release. However, elevated mitochondrial Ca2+ loading, oxidative stress, and mitochondrial depolarization are critical factors leading to mPTP opening/activation. Although the exact mechanism underlying mPTP-mediated cell death remains elusive, mPTP-mediated apoptosis machinery has been considered as an important clamp and plays a critical role in the pathogenesis of several types of cancers. In this review, we focus on structure and regulation of the mPTP complex-mediated apoptosis mechanisms and follow with a comprehensive discussion addressing the development of novel mPTP-targeting drugs/molecules in cancer treatment.

The nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) has shown promising pharmacological activities, including inhibition of cancerous cell growth and N-glycosylation. It has been used as a glycolysis inhibitor and as a potential energy restriction mimetic agent, inhibiting pathogen-associated molecular patterns. Radioisotope derivatives of 2-DG have applications as tracers. Recently, 2-DG has been used as an anti-COVID-19 drug to lower the need for supplemental oxygen. In the present review, various pharmaceutical properties of 2-DG are discussed.

Mitochondria are organelles that serve as a central hub for physiological processes in eukaryotes, including production of ATP, regulation of calcium dependent signaling, generation of ROS, and regulation of apoptosis. Cancer cells undergo metabolic reprogramming in an effort to support their increasing requirements for cell survival, growth, and proliferation, and mitochondria have primary roles in these processes. Because of their central function in survival of cancer cells and drug resistance, mitochondria are an important target in cancer therapy and many drugs targeting mitochondria that target the TCA cycle, apoptosis, metabolic pathway, and generation of ROS have been developed. Continued use of mitochondrial-targeting drugs can lead to resistance due to development of new somatic mutations. Use of drugs is limited due to these mutations, which have been detected in mitochondrial proteins. In this review, we will focus on genetic mutations in mitochondrial target proteins and their function in induction of drug-resistance.

Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success.

In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells.

The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity.

Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.

Although platelets are anucleated cells, they have fully functional mitochondria, and currently, it is known that several processes that occur in the platelet require the action of mitochondria. There are plenty of mitochondrial-targeted compounds described in the literature related to cancer, however, only a small number of studies have approached their interaction with platelet mitochondria and/or their effects on platelet activity. Recent studies have shown that magnolia extract and mitochondria-targeted magnolol can inhibit mitochondrial respiration and cell proliferation in melanoma and oral cancer cells, respectively, and they can also induce ROS and mitophagy. In this study, the effect of triphenylphosphonium cation, linked by alkyl chains of different lengths, to the organic compound magnolol on human-washed platelets was evaluated. We demonstrated that the addition of triphenylphosphonium by a four-carbon linker to magnolol (MGN4) considerably enhanced the Magnolol antiplatelet effect by a 3-fold decrease in the IC50. Additionally, platelets exposed to MGN4 5 µM showed several differences from the control including increased basal respiration, collagen-induced respiration, ATP-independent respiration, and reduced ATP-dependent respiration and non-mitochondrial respiration.

Triphenylphosphonium (TPP⁺) conjugated compounds selectively target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. To date, studies have focused on modifying either the linker or the cargo of TPP⁺-conjugated compounds. Here, we investigated the biological effects of direct modification to TPP⁺ to improve the efficacy and detection of mito-metformin (MMe), a TPP⁺-conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells. We designed, synthesized, and tested trifluoromethyl and methoxy MMe analogs (pCF₃-MMe, mCF₃-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF₃-MMe showed enhanced selectivity toward cancer cells compared to MMe, while retaining the same signaling mechanism. Importantly, pCF₃-MMe allowed quantitative monitoring of cellular accumulation via ¹⁹F-NMR in vitro and in vivo. Furthermore, adding trifluoromethyl groups to TPP⁺ reduced toxicity in vivo while retaining anti-tumor efficacy, opening an avenue to de-risk these next-generation TPP⁺-conjugated compounds.

Aberrant energy metabolism not only endows tumor cells with unlimited proliferative capacity but also contributes to the establishment of the glucose-deficient/lactate-rich immunosuppressive tumor microenvironment (ITM) impairing antitumor immunity. Herein, a novel metabolic nanoregulator (D/B/CQ@ZIF-8@CS) was developed by enveloping 2-deoxy-d-glucose (2-DG), BAY-876, and chloroquine (CQ) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously deprive the energy/nutrition supply of tumor cells and relieve the ITM for synergetic tumor starvation-immunotherapy. Aerobic glycolysis, glucose uptake, and autophagy flux could be concurrently blocked by D/B/CQ@ZIF-8@CS, cutting off the nutrition/energy supply and the source of lactate. Furthermore, inhibition of glucose uptake and aerobic glycolysis could effectively reverse the glucose-deficient/lactate-rich ITM, thus functionally inactivating regulatory T cells and augmenting anti-CTLA-4 immunotherapy. Such a two-pronged strategy would provide new insights for the design of metabolic intervention-based synergistic cancer therapy.

Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and histone deacetylases (HDACs), exhibiting anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein, we report the design and identification of a novel 4-CF₃-phenyl triphenylphosphonium-based PBA conjugate (53) with improved in vitro and in vivo anticancer activities. Compound 53 exhibited an IC₅₀ value of 2.22 μM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In the A375 cell-derived xenograft mouse model, 53 reduced the tumor growth by 76% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for cancer therapy.

Mitochondrial dysfunction, characterized by the electron transport chain (ETC) leakage and reduced adenosine tri-phosphate synthesis, occurs primarily due to free radicals -induced mutations in either the mitochondrial deoxyribonucleic acid (mtDNA) or nuclear (n) DNA caused by pathogenic infections, toxicant exposures, adverse drug-effects, or other environmental exposures, leading to secondary dysfunction affecting ischemic, diabetic, cancerous, and degenerative diseases. In these concerns, mitochondria-targeted remedies may include a significant role in the protection and treatment of mitochondrial function to enhance its activity. Coenzyme Q10 pyridinol and pyrimidinol antioxidant analogues and other potent drug-compounds for their multifunctional radical quencher and other anti-toxic activities may take a significant therapeutic effectivity for ameliorating mitochondrial dysfunction. Moreover, the encapsulation of these bioactive ligands-attached potent compounds in vesicular system may enable them a superb biological effective for the treatment of mitochondria-targeted dysfunction-related diseases with least side effects. This review depicts mainly on mitochondrial enzymatic dysfunction and their amelioration by potent drugs with the usages of nanoparticulated delivery system against mitochondria-affected diseases.

Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.

Herein, we combined a derivative of cisplatin (CP) and the chemosensitizer lonidamine (LND) to design an amphiphilic prodrug, in which the ratio of LND to cisplatin was fixed at 2:1. Diaminedichlorodihydroxyplatinum (DH-CP) is a hydrophilic cisplatin derivative. Due to its appropriate amphiphilicity, this prodrug could self-assemble into stable nanoparticles (denoted as LNP-NPs). Under the action of excessive glutathione (GSH) in tumor cells, DH-CP could be reduced to cytotoxic cisplatin. In addition, the released LND could inhibit the metabolic process of tumor cells, and improving the sensitivity of tumor cells to cisplatin. In vitro studies demonstrated that LNP-NPs displayed significantly cytotoxicity on breast cancer cells, and the cell viability after co-incubation for 48 h (CP 16 μg/mL) were 18.77% (MCF-7) and 20.01% (EMT6), respectively. LNP-NPs could also significantly inhibit the growth of MCF-7 tumor-like spheroids, which were realized through the high coordination and cooperation between CP and LND. Therefore, the carrier-free drug delivery system based on LND and DH-CP is expected to achieve a good synergistic anti-tumor effect.

Chloroethylnitrosoureas (CENUs) exert antitumor activity via producing dG-dC interstrand crosslinks (ICLs). However, tumor resistance make it necessary to find novel strategies to improve the therapeutic effect of CENUs. 2-Deoxy-D-glucose (2-DG) is a well-known glycolytic inhibitor, which can reprogram tumor energy metabolism closely related to tumor resistance. Here, we investigated the chemosensitization effect of 2-DG on l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against glioblastoma cells and the underlying mechanisms. We found that 2-DG significantly increased the inhibitory effects of BCNU on tumor cells compared with BCNU alone, while 2-DG showed no obvious enhancing effect on the BCNU-induced cytotoxicity for normal HaCaT and HA1800 cells. Proliferation, migration and invasion determinations presented the same trend as survival on tumor cells. 2-DG plus BCNU increased the energy deficiency through a more effective inhibition of glycolytic pathway. Notably, the combination of 2-DG and BCNU aggravated oxidative stress in glioblastoma cells, along with a significant decrease in glutathione (GSH) levels, and an increase in intracellular reactive oxygen species (ROS). Subsequently, we demonstrated that the combination treatment led to increased apoptosis via activating mitochondria and endoplasmic reticulum stress (ERS) related apoptosis pathways. Finally, we found that the dG-dC level was significantly increased after 2-DG pretreatment compared to BCNU alone by HPLC-ESI-MS/MS analysis. Finally, in vivo, 2-DG plus BCNU significantly suppressed tumor growth with lower side effects compared with BCNU alone in tumor-bearing mice. In summary, we proposed that 2-DG may have potential to increase the sensitivity of glioblastoma cells to BCNU by regulating glycolysis, ROS and ERS pathways in clinical setting.

Breast cancer is the leading cause of death in women around the world. Its occurrence and development have been linked to genetic factors, living habits, health conditions, and socioeconomic factors. Comparisons of incidence and mortality rates of female breast cancer are useful approaches to define cancer-related socioeconomic disparities.

This was a retrospective observational cohort study on breast cancer of women in several developed countries over 30 years. Effects of socioeconomic factors were analyzed using a path diagram method.

We found a positive, significant association of public wealth on incidence and mortality of breast cancer, and the path coefficients in the structural equations are -0.51 and -0.39, respectively. The unemployment rate (UR) is critical and the path coefficients are all 0.2. The path coefficients of individual economic wealth to the rates of breast cancer are 0.18 and 0.27, respectively.

The influence of social pressure on the incidence and mortality of breast cancer was not typical monotonous. The survival rate of breast cancer determined by the ratio of mortality rate to incidence rate showed a similar pattern with socioeconomic factors.

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.

Cancer remains a health-related concern globally from the ancient times till to date. The application of light to be used as therapeutic potential/agent has been used for several thousands of years. Photodynamic therapy (PDT) is a modern, non-invasive therapeutic modality for the treatment of various infections by bacteria, fungi, and viruses. Mitochondria are subcellular, double-membrane organelles that have the role in cancer and anticancer therapy. Mitochondria play a key role in regulation of apoptosis and these organelles produce most of the cell's energy which enhance its targeting objective. The role of mitochondria in anticancer approach is achieved by targeting its metabolism (glycolysis and TCA cycle) and apoptotic and ROS homeostasis. The role of mitochondria-targeted cancer therapies in photodynamic therapy have proven to be more effective than other similar non-targeting techniques. Particularly in PDT, mitochondria-targeting sensitizers are important as they have a crucial role in overcoming the hypoxia factor, resulting in high efficacy. IR-730 and IR-Pyr are the indocyine derivatives photosensitizers that play a crucial role in targeting mitochondria because of their better photostability during laser irradiation. Clinical and pre-clinical trials are going on this approach to target different solid tumors using mitochondrial targeted photodynamic therapy.