Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

Supplementary Figure 1. The levels of proteins and enzyme subunits involved in OXPHOS and glutamine metabolism increase with lung tumor progression. A, Representative H&E and IHC images of lung tissue sections from KLLuc mice showing levels of the OXPHOS protein HCCS. B, Representative H&E and IHC images of lung tissue sections from KLLuc mice showing levels of the glutamine transporter SLC1A5. C, Representative H&E and IHC images of lung tissue sections from KLLuc mice showing levels of GLS. Shown are montage images of lung tissue sections stained with H&E (row 1), montage images stained with DAPI (row 2) or antibodies against the indicated protein (row 3), and 10X images of lung tissue sections stained with DAPI (row 4) or antibodies against the indicated protein (row 5). The light green lines in DAPI montage images outline the tumors in the lung. The blue rectangles in H&E and white rectangles in DAPI montage images denote the regions shown in 10X. Scale bar, montage, 1mm; 4X, 200 µm; 10X, 100µm. D, Graph showing quantified levels of HCCS correlating with A. E, Graph showing quantified levels of SLC1A5 correlating with B. F, Graph showing quantified levels of GLS correlating with C. Protein levels were quantified, and data are plotted as mean {plus minus} SEM. G, Representative 40X IHC images of lung tissue sections showing the co-localization of ATP5F1A, COX7B, and CYCS with the mitochondrial marker TOMM20. Scale bar, 10 µm. H, OCR of NSCLC H226 cells cultured in normal medium, or heme depleted medium with 0.5 mM succinyl acetone (HD+SA). Heme (5 µM, 10 µM, and 20 µM, respectively) was added back to examine the effects of heme on OCRs. For statistical analysis, the levels in cells with heme added back were compared with the levels in cells without heme added back with a Welch two-sample t test. **, P<0.005.

Supplementary Figure 3. The levels of heme synthesis (A), heme uptake (B), and oxygen consumption rate (OCR, C) in SCC cell lines are comparable to the levels of ADC cell lines.

We identified an important oncogenic role for protocadherin 7 (PCDH7), a cell surface protein frequently overexpressed in lung adenocarcinoma and associated with poor clinical outcome. Pcdh7 depletion reduces tumor burden and prolongs survival in Kras ^LSL-G12D ; Tp53 ^fl/fl mice. These findings nominate this cell surface protein as an actionable therapeutic target and highlight the therapeutic potential of PCDH7 inhibition for non–small cell lung cancer. We report the development and characterization of high-affinity anti-PCDH7 monoclonal antibodies (mAbs) that inhibit downstream mitogen-activated protein kinase (MAPK) pathway activation and suppress tumor growth in multiple mutant KRAS –driven models. A lead mAb (mAb7) sensitized tumors to the US Food and Drug Administration–approved MAPK kinase inhibitor trametinib and the KRAS ^G12C inhibitor adagrasib. A humanized mAb7-IgG1 (Hu-mAb7) exhibited antibody-dependent cellular cytotoxicity and Fc-mediated immune effector killing of tumor cells in vivo. Moreover, a murinized antibody (Ms-mAb7) improved antitumor immunity in a Kras ^G12D syngeneic tumor model by enhancing infiltration and activation of cytotoxic immune cells. These findings provide an important advance in the clinical development of PCDH7-targeting antibodies for lung cancer treatment.