Mitochondria undergo constant fission and fusion cycles according to the cellular bioenergetic situation. This fine-tuning of mitochondria is vital to give cells the optimal energy supply and survival. The mitochondrial architecture principally consists of optical atrophy 1 (OPA1), mitofusin 1/2 (Mfn1/2), the mitochondrial fission controlled by dynamin-related protein 1 (Drp1), and its mitochondrial adaptor fission protein 1 (Fis1) (Santel and Fuller, 2001; Chen and Chan, 2005; Loson et al., 2013).

C1QBP modulates mitochondrial morphology and integrity. C1qbp silencing not only promoted mitochondrial fragmentation but also repressed mitochondrial fusion (Fogal et al., 2010; Li et al., 2011; Hu et al., 2013; Noh et al., 2020). For example, Solhee Noh et al. found that genetic ablation of C1QBP activates the overlapping activity with m-AAA protease (OMA1) to cleave OPA1, which leads to mitochondrial fragmentation and swelling (Noh et al., 2020). C1QBP regulated mitochondrial morphology by regulating OMA1‐dependent proteolytic processing of OPA1. On the other hand, MengJie Hu et al. revealed that overexpression of C1QBP increased mitochondrial fibrils (Hu et al., 2013). At the same time, C1QBP siRNA-treated cells contained predominantly small spherical mitochondria compared with the mainly normal elongated mitochondria in control cells. To further explore the underlying mechanism, they examined the expression of Mfn1, Mfn2, and mitochondrial Drp-1 and found that the C1QBP siRNA treatment resulted in a detectable loss of Mfn1 and Mfn2 and decreased Drp-1 levels. Here, siRNA-mediated C1qbp knockdown induced a more punctate mitochondrial morphology, which was associated with the reduction of the mitochondrial fusion mediator proteins, a sign of potential subsequent degradation.

Some tumor cells significantly depend on mitochondrial-mediated oxidative phosphorylation (Funes et al., 2007; Moreno-Sanchez et al., 2007). Since oxidative metabolism may recycle lactate, mitochondrial metabolism is advantageous for tumor cells that are highly glycolytic (Sonveaux et al., 2008). Moreover, glycolytic pathway oncogenes may upregulate some genes encoding mitochondrial proteins or those involved in mitochondrial biogenesis (Li et al., 2005). Additionally, mitochondria regulate cellular bioenergetic and biosynthetic processes of important cancer signaling pathways, such as proliferation, metastasis and self-renewal (Viale et al., 2014; Liu and Shi, 2020). Collectively, these findings suggest that oncogene-driven glycolytic metabolism should be balanced, at least in part, by concomitant changes to mitochondria. Mitochondrial metabolism may potentiate cellular plasticity and metabolic flexibility to deal with the relentless microenvironment.

C1QBP plays an indispensable role in mitochondrial function and metabolic regulation. For example, C1qbp-deficient mouse embryonic fibroblasts (MEFs) cells exhibit reduced OXPHOS function (Yagi et al., 2012). A mutation of C1qbp has also been suggested as a cause of mitochondrial respiratory chain disorder. In this regard, C1QBP is a crucial regulator of mitochondria-mediated OXPHOS.

A functional mitochondrial network responding to physiological adaptations and stress conditions is critical for a healthy cellular condition. Given that mitochondria are exposed to high levels of reactive oxygen species, they have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria are present to meet cellular demands. Mitochondria eliminate the damaged mitochondrial proteins through autophagy. Thus, understanding how C1QBP orchestrates mitophagy to maintain mitochondrial homeostasis could provide critical insights.

Jiao et al. (2015) reported that C1QBP controlled mitochondrial autophagy to help cells adapt better to the challenging microenvironment (Jiao and You, 2016). Serine/threonine kinase Unc-51-like kinase-1 (ULK1) is crucial in inducing mitophagy. This protein is susceptible to proteasome-mediated degradation. C1QBP regulates ULK1 stability by forming a protein complex with ULK1. The interaction between ULK1 and C1QBP is indispensable to maintaining steady-state levels of ULK1, thereby preventing its polyubiquitylation. Moreover, it has been shown that mitophagy defects can be recovered by re-introducing ULK1 into C1QBP-deficient cells, which suggested that C1QBP protected mitophagy through the prevention of ULK1 degradation. Considering that mitochondrial homeostasis and oxidative phosphorylation might be mutually beneficial (Wrighton, 2013), mitochondrial quality control may serve as an important mechanism for maintaining cellular energy homeostasis. Therefore, C1QBP exerts a protective effect under starvation conditions by both inducing Ulk1-dependent autophagy and maintaining oxidative phosphorylation. In this regard, C1QBP-Ulk1-mitophagy axis may provide a survival advantage when nutrients are scarce, which ultimately promotes tumorigenesis.

Taken together, mitochondrial plasticity including mitochondrial dynamics, metabolism, and autophagy is tightly linked to mitochondrial structure, function and homeostasis. C1QBP overexpression promotes mitochondrial plasticity to endow tumor cells with proliferation and malignant progression. On the contrast, C1qbp knocking down dampens mitochondrial adaptation and metabolic flexibility, which is responsible for tumor repression.

Dendritic cells (DCs) have different functions, and among them are the following ones: 1) constitute the most potent antigen-presenting cells; 2) induce primary immune responses; 3) capture antigens in peripheral tissues; 4) recognize pathogen-associated molecular patterns of invading microbes post-Toll-like receptors (TLRs) ligation, which leads to cellular activation and changes in gene expression and cellular metabolism in DCs (Banchereau et al., 2000; Kawai and Akira, 2011). Gotoh et al. (2018) reported that C1QBP was indispensable in DCs metabolism and maturation. Their study found that mitochondrial C1QBP and pyruvate dehydrogenase (PDH) activity are necessary for DC maturation both in vitro and in vivo. Although pyruvate and lactate were similarly produced by both W.T. and C1qbp ^−/− DCs, after lipopolysaccharide (LPS) stimulation, LPS-induced citrate production was impaired C1qbp ^−/− DCs. Generally, glucose is processed by the cytosolic glycolytic pathway to generate pyruvate. Acetyl-coenzyme A (acetyl-CoA) is produced from pyruvate by the PDH complex and subsequently reacts with oxaloacetate to form citrate in mitochondria. Given that after LPS stimulation, the upstream metabolites of citrate in wild type (WT) and C1qbp ^−/− DCs were produced at similar levels, the authors focused on the activity of PDH in both DCs types. They revealed that C1QBP could bind to PDH-E2 in DCs by immunoprecipitation experiments. Furthermore, the PDH activity in WT was significantly higher than that in C1qbp ^−/− DCs at the basal condition, which means C1QBP may control PDH activity by binding to PDH-E2 to regulate citrate production and further support DC. maturation. Notably, PDH-mediated citrate production from pyruvate is involved in fat acid synthesis (FAS). This mechanism impacts the endoplasmic reticulum (ER) expansion. Interestingly, ER expansion was observed in WT DCs but not in C1qbp ^−/− DCs after LPS stimulation.

Therefore, C1QBP bound to PDH-E2 promoted the activity of PDH, facilitating citrate production and enhancing FAS and ER expansion. In this regard, C1QBP involvement in regulating DCs maturation by controlling mitochondrial metabolism other than the electron transport chain (ETC) has many consequences to help fine-tune mitochondria expression, and alterations could lead to the decreased immune function of DCs.

Besides DCs maturation, C1QBP was also reported to be implicated in the regulation of T cells differentiation. Zhai et al. (2021) revealed that C1QBP was involved in the modulation of effector CD8⁺ T cells differentiation to affect their antiviral and antitumor immune responses further. Firstly, C1qbp deficiency in T cells intrinsically impaired the differentiation of effector CD8⁺ T cells, which is attributed to a failure to increase their mitochondrial respiratory capacities. They found that activated CD8⁺ T cells had greater glycolytic and OXPHOS requirements than activated CD4⁺ T cells and were more sensitive to OXPHOS impairment. In other words, C1QBP-mediated augmentation of OXPHOS was necessary for the differentiation of effector CD8⁺ T cells. Moreover, C1QBP promoted the epigenetic and transcriptional programs of effector CD8⁺ T cells. It achieved it by controlling the production of metabolites, including acetyl-CoA, fumarate, and 2-HG. Their study revealed that C1qbp deficiency mediated OXPHOS impairment. This, in turn, capitulated in decreased acetyl-CoA but increased fumarate and 2-HG. Moreover, downregulation of acetyl-CoA subsequently dampens histone protein H3K27 acetylation, which enhances CpG methylation to reduce some genes expression encoding several master transcription factors that drive effector CD8⁺ T cell differentiation such as Id2, Prdm1, and Tbx21.

Consequently, CD8⁺ T cell differentiation becomes retarded. C1QBP facilitates the epigenetic and transcriptional programs of effector CD8⁺ T cells differentiation by controlling metabolites coupled to OXPHOS. In this regard, they provide a mechanistic association between mitochondrial metabolism and CD8⁺ T cell differentiation, which means these metabolite supplementations or targeting OXPHOS may have significant application in T cell therapies for cancer.

Tumor-infiltrating T cells encounter not only persistent tumor antigen but also experience metabolic stress from the tumor microenvironment such as glucose competition, metabolite accumulation, and hypoxia (Vardhana et al., 2020; Yu et al., 2020). Scharping et al. (2016) revealed that continuous antigen stimulation, coordinated with hypoxia, impaired mitochondrial functions to drive T cells terminal exhaustion. Although hypoxia alone cannot induce T cells dysfunction, its association with persistent antigen stimulation plays a fundamental role in T cells exhaustion. While on the one hand, the tumor microenvironment makes tumor-infiltrating T cells with dysfunctional mitochondria have a lower mass and activity (measured as spare respiratory capacity), driving T cells’ metabolic insufficiency. On the other hand, the continuous activation of tumor-infiltrating cells further increases mitochondrial reactive oxygen species (ROS) to exacerbate the exhausted phenotype of tumor-specific T cells. Of note, mitigating hypoxia effectively alleviates these tumor-infiltrating T cells exhaustion. Mitochondria has a fundamental role in modulating T cells’ development, fate, and function. Fine-tuning mitochondria is critical for altering the different metabolic preferences and activities within cells. Recently it was shown that impaired ATP production and accumulation of mitochondrial ROS in dysfunctional T cells within the suppressive tumor microenvironment aggravated T cells exhaustion (Li et al., 2020; Vardhana et al., 2020). However, the relationship between metabolic stress and T cell exhaustion remains still unclear.

The question of whether the mitochondrial protein C1QBP is implicated with T cells exhaustion is interesting. Our previous study found that C1qbp knockdown modulated T cells with the accumulation of ROS and the loss of mitochondrial membrane potential, thus impairing T cell mitochondrial fitness (Tian et al., 2022). At the same time, C1QBP insufficiency aggravated exhausted T cells. We assessed exhaustion markers, such as PD-1, Tim-3, and LAG-3 in these tumor-specific T cells. We found that these inhibitory receptors exhibited higher expression levels in tumor-infiltrating C1qbp ^+/− T cells than the corresponding WT cells. In this regard, C1qbp knocking down exacerbated the tumor-infiltrating T cells exhaustion, leading to a reduced antitumor immune response.

Chronic antigen stimulation drives the defective oxidative phosphorylation and promotes ROS generation in activated T cells, so C1qbp could dampen T cells proliferation while remaining susceptible to cellular apoptosis. To detect the underlying molecular mechanism, we noticed AKT/mTOR proliferation signaling pathway and Bcl-2 anti-apoptotic signaling pathway. Our previous results demonstrated that C1qbp insufficiency inhibited the AKT/mTOR signaling pathway, which conferred T cells with relatively weaker proliferation capacity (Tian et al., 2022). At the same time, C1qbp knocking down reduced the anti-apoptotic proteins recruitment, such as Bcl-2 and Bcl-XL, but aggravated caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage, which thus accelerated T cells apoptotic process. Therefore, C1qbp knockdown induces T cells exhaustion and pre-apoptosis but retarded their proliferation as well as antitumor immune function.

Overall, the potentiation of immune cells’ mitochondrial plasticity through C1QBP promotes fatty acid metabolism, ER expansion, and mitochondrial OXPHOS, but relieves the accumulation of ROS, which could further enhance the DCs maturation, T cells differentiation as well as the tumor-infiltration T cells durability (Figure 1 ).

C1QBP is involved in tumor progression and metastasis, making it an attractive, actionable target against cancer, bringing to the development of monoclonal antibodies (mAbs). Such therapies were successful in inhibiting tumor growth and migration (Sanchez-Martin et al., 2011). The unique upregulation of C1QBP in certain tumors, and targeting it, in various ways, in such tumors could be a valuable strategy (Yenugonda et al., 2017; Rousso-Noori et al., 2021). C1QBP can also be found at the cell surface of angiogenic endothelial cells besides tumor cells. In nature, C1QBP acts as a receptor bound by the CGKRK peptide. Based on such premises, Agemy et al. devised a tumor-targeted nanosystem, through which CGKRK pentapeptide delivers a proapoptotic peptide into the mitochondria of tumor blood vessel endothelial cells and tumor cells (Agemy et al., 2013). The treatment was highly effective, especially in the refractory glioblastoma mouse models, compared to other antiangiogenic therapies.

Moreover, another tumor-homing peptide, LyP-1 (CGNKRTRGC), capable of targeting the cell surface of localized C1QBP, has been used to deliver nanoparticles to breast tumors overexpressing C1QBP and has shown efficacy in vivo (Luo et al., 2010). However, both the anti-C1QBP antibody and the LyP-1 peptide targeted the C1QBP subset that was exposed on the cell surface. Yenugonda et al. (2017) developed C1QBP-directed therapeutics to inhibit the protein in all subcellular compartments, including mitochondria. A primary screening assay employing a glutamine-addicted glioma cell line identified a hit compound called M36, which could bind and inhibit C1QBP located on the cellular membrane and in the mitochondria. In addition, they further demonstrated that M36 impedes the growth of glioma cells and patient-derived glioma stem cells in culture due to C1QBP genetic knockdown.

In addition, antibody neutralization of C1QBP inhibits lamellipodia formation, cell migration and focal adhesion kinase activation (Kim et al., 2016). At the same time, this antigen-antibody reaction inactivates receptor tyrosine kinases (RTKs) activation in various cancer cells and prevents even angiogenesis, resulting in the decreased tumorigenesis in vivo. Notably, A novel tumor penetrating peptide, linTT1 (AKRGARSTA), as a tumor targeting ligand for nanoparticles (Sharma et al., 2017). C1QBP as the primary homing receptor for linTT1, is expressed on the cell surface of peritoneal carcinoma cell lines (Paasonen et al., 2016). Iron oxide nanoworms (NWs) functionalized with the linTT1 peptide in tandem with a pro-apoptotic peptide showed C1QBP-dependent cytotoxicity (Hunt et al., 2017). At the same time, the linTT1-NWs predominantly accumulates in CD31-positive blood vessels, in LYVE-1-positive lymphatic structures, and in CD11b-positive tumor macrophages, thus resulting in significant reduction of weight of peritoneal tumors and significant decrease in the number of metastatic tumor nodules. In this regard, C1QBP-directed intraperitoneal targeting of other anticancer agents may represent a potential strategy to improve their therapeutic index.

Considering that C1QBP is be specifically expressed on the surface of glioma cells, it is regarded as a suitable tumor associated antigen (TAA) for redirected chimeric antigen receptor (CAR) T cell therapy. Rousso-Noori et al. (2021) reported that C1QBP-specific CAR T cells exerted a dual antitumor and antiangiogenic therapeutic benefit in gliomas. Their study focused on designing CAR T cells targeting C1QBP positive glioma cells. They found that the CAR T cells targeting C1QBP reduced tumor vascularization and extended the overall survival of mice bearing gliomas, thus providing proof-of-principle evidence that C1QBP-CAR T cells can recognize and eliminate not only glioma cells but also tumor endothelial cells. Thus, CAR T cells targeting C1QBP may serve as a therapeutic option for glioblastoma patients through specifically recognizing and eliminating C1QBP expressing glioma cells and tumor derived endothelial cells, finally controlling tumor growth in orthotopic syngeneic and xenograft mouse models.

On the other hand, upregulation of mitochondrial plasticity may effectively reinvigorate T cell’s robust and persistent immune function. This could alter the metabolic competition between tumor cells and immune systems. Thus, it is worth noting that C1QBP modified CAR T cells’ immune function and their long-term maintenance. Our previous study demonstrated that C1qbp knockdown attenuated CAR T cells’ antitumor immune response (Tian et al., 2022). Specifically, we constructed the C1qbp ^+/− and C1qbp ^+/+ CAR T cells targeting B7-H3. We found that C1qbp knocking down reduced CAR T cells’ release of IFN-γ and TNF-α cytokines, which reduced the corresponding immunotherapeutic efficacy of CAR T cells in vivo. In contrast, sufficient C1qbp potentiated CAR T cells’ mitochondrial adaptation to the relentless TME by ameliorating their exhaustion, thereby improving their durable antitumor immune function.

Since the mitochondrial function and metabolic flexibility imply the fate and function of immune cells, metabolic interventions manipulating immunity are rare. Using new proteins to achieve this purpose represents a great opportunity that remains untapped. Therefore, developing strategies for potentiation of mitochondrial-dependent metabolic flexibility could improve the efficacy of current immune-based anticancer therapy.