Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.
Saved in:
| Title: | Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity. |
|---|---|
| Authors: | You, Zhiyuan (AUTHOR), Kim, Jiyeon (AUTHOR), Guo, Chuansheng (AUTHOR), Hu, Haoran (AUTHOR), Chapman, Nicole M. (AUTHOR), Meng, Xiaoxi (AUTHOR), Shi, Hao (AUTHOR), Wang, Yan (AUTHOR), Guy, Cliff (AUTHOR), KC, Anil (AUTHOR), Li, Jia (AUTHOR), Saravia, Jordy (AUTHOR), Palacios, Gustavo (AUTHOR), Rankin, Sherri (AUTHOR), Robinson, Camenzind G. (AUTHOR), Chi, Hongbo (AUTHOR) |
| Source: | Science. 4/2/2026, Vol. 392 Issue 6793, p1-20. 20p. |
| Subjects: | Mitochondrial proteins, Dendritic cells, Immune checkpoint inhibitors, Immunotherapy, Immunity, Electron transport, Mitochondrial physiology |
| Abstract: | Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8+ T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD+/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy. Editor's summary: Type 1 conventional dendritic cells (cDC1s) promote CD8+ T cell–mediated antitumor responses. However, cDC1s can become dysfunctional in the tumor microenvironment, and the mechanisms governing cDC1 function versus dysfunction in cancer remain unclear. You et al. report that mitochondrial metabolic states and signaling direct cDC1 function in antitumor immunity (see the Perspective by Molina and Haldar). Loss of the mitochondrial protein OPA1 disrupted nuclear respiratory factor 1 (NRF1) activity and electron transport chain integrity, leading to defects in mitochondrial bioenergetics and redox balance in cDC1s, accompanied by reduced tumor control. OPA1-NRF1 signaling progressively declined during tumor progression, and tumor-bearing mice receiving cDC1s with high mitochondrial fitness had improved antitumor responses, especially in combination with immunotherapy. Therefore, "metabolic engineering" of cDC1s may provide a mechanism for cancer immunotherapy. —Priscilla N. Kelly INTRODUCTION: Conventional type 1 dendritic cells (cDC1s) are essential for cytotoxic CD8+ T cell responses in cancer immunity and immunotherapy. Although previous studies have suggested that mitochondrial oxidative phosphorylation (OXPHOS) is dispensable for DC maturation in vitro and represents a hallmark of tolerance in human monocyte–derived DCs, whether and how mitochondrial metabolism regulates cDC1-CD8+ T cell interactions in antitumor immunity remain largely unknown. In this study, we reveal that intratumoral cDC1s have discrete mitochondrial states and that mitochondrial fusion protein OPA1 dictates cDC1 antitumor immunity by facilitating mitochondrial energy and redox metabolism. RATIONALE: Despite the success of immunotherapy in cancer treatment, therapeutic resistance or relapse occurs in a large subset of patients. cDC1s determine antitumor effects and therapeutic benefits upon immune checkpoint blockade (ICB) by orchestrating CD8+ T cell activation and function. However, cDC1s often experience metabolic stress and exhibit decreased functional fitness within the tumor microenvironment. In this study, we aimed to identify key metabolic regulators that promote cDC1-dependent antitumor responses, which represent putative targets to metabolically engineer cDC1s to combat cancer, especially in combination with ICB therapy. RESULTS: We established, from both mouse and human tumors, that cDC1s exhibit discrete mitochondrial states. One subpopulation, referred to as [TMRM/MG]hi cells, contained polarized mitochondria, as demonstrated by the ratio of mitochondrial membrane potential [measured with tetramethylrhodamine methyl ester perchlorate (TMRM)] compared with mitochondrial mass [measured with MitoTracker Green (MG)]; whereas the other subpopulation, [TMRM/MG]lo cells, had depolarized mitochondria. Intratumoral cDC1s with polarized mitochondria more effectively primed CD8+ T cell responses than those with depolarized mitochondria. Using unbiased profiling approaches and experimental validations, we uncovered that OPA1 orchestrates the mitochondrial states and morphology in intratumoral cDC1s. Notably, OPA1 deletion in cDC1s led to increased tumor growth and impaired antitumor CD8+ T cell responses, corresponding to defective antigen presentation by cDC1s. Mechanistically, we established that OPA1 supports nuclear respiratory factor 1 (NRF1) activity and expression to sustain mitochondrial OXPHOS in cDC1s. OPA1-NRF1 axis–mediated OXPHOS inhibited autophagy and lysosome–dependent degradation of major histocompatibility complex I (MHC-I) and antigen. In addition, OPA1-mediated electron transport chain (ETC) flow contributed to cDC1 immunogenicity by facilitating NADH-to-NAD+ conversion (i.e., conversion from the reduced to the oxidized form of nicotinamide adenine dinucleotide). These OPA1-dependent effects were antagonized by mitochondrial fission protein DRP1. During tumor progression, intratumoral cDC1s experienced a progressive mitochondrial dysfunction, as revealed by reduction of the [TMRM/MG]hi subpopulation as well as decreased mitochondrial volume and OPA1-NRF1 signaling. Intratumoral administration of tumor antigen–pulsed cDC1s with polarized mitochondria into tumor-bearing mice resulted in superior tumor control compared with cDC1s with depolarized mitochondria, particularly when combined with ICB therapies. Indeed, a substantial proportion of mice receiving cotreatment of tumor antigen–pulsed cDC1s with polarized mitochondria plus ICB completely rejected tumors and developed durable immune memory responses upon tumor rechallenge. CONCLUSION: We uncovered discrete mitochondrial states and the underlying mitochondrial metabolic signaling programs in cDC1s that support their functional fitness in antitumor immunity and the establishment of durable ICB responses. These discoveries provide opportunities to reinvigorate cDC1s for improved cancer immunotherapy. Mitochondrial metabolism and signaling orchestrate cDC1 antitumor responses.: (Left) [TMRM/MG]hi cDC1s more effectively prime CD8+ T cell responses and control tumor growth compared with [TMRM/MG]lo cells. Intratumoral cDC1s undergo mitochondrial dysfunction and decreased OPA1-NRF1 signaling during tumor progression. (Right) The OPA1-NRF1 axis maintains OXPHOS to inhibit autophagy and lysosome–mediated degradation of MHC-I and antigen. OPA1-mediated ETC flow also supports cDC1 immunogenicity by balancing the NAD+/NADH ratio. These effects are antagonized by DRP1. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
| Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
|
Full text is not displayed to guests.
Login for full access.
|
|
| Abstract: | Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8+ T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD+/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy. Editor's summary: Type 1 conventional dendritic cells (cDC1s) promote CD8+ T cell–mediated antitumor responses. However, cDC1s can become dysfunctional in the tumor microenvironment, and the mechanisms governing cDC1 function versus dysfunction in cancer remain unclear. You et al. report that mitochondrial metabolic states and signaling direct cDC1 function in antitumor immunity (see the Perspective by Molina and Haldar). Loss of the mitochondrial protein OPA1 disrupted nuclear respiratory factor 1 (NRF1) activity and electron transport chain integrity, leading to defects in mitochondrial bioenergetics and redox balance in cDC1s, accompanied by reduced tumor control. OPA1-NRF1 signaling progressively declined during tumor progression, and tumor-bearing mice receiving cDC1s with high mitochondrial fitness had improved antitumor responses, especially in combination with immunotherapy. Therefore, "metabolic engineering" of cDC1s may provide a mechanism for cancer immunotherapy. —Priscilla N. Kelly INTRODUCTION: Conventional type 1 dendritic cells (cDC1s) are essential for cytotoxic CD8+ T cell responses in cancer immunity and immunotherapy. Although previous studies have suggested that mitochondrial oxidative phosphorylation (OXPHOS) is dispensable for DC maturation in vitro and represents a hallmark of tolerance in human monocyte–derived DCs, whether and how mitochondrial metabolism regulates cDC1-CD8+ T cell interactions in antitumor immunity remain largely unknown. In this study, we reveal that intratumoral cDC1s have discrete mitochondrial states and that mitochondrial fusion protein OPA1 dictates cDC1 antitumor immunity by facilitating mitochondrial energy and redox metabolism. RATIONALE: Despite the success of immunotherapy in cancer treatment, therapeutic resistance or relapse occurs in a large subset of patients. cDC1s determine antitumor effects and therapeutic benefits upon immune checkpoint blockade (ICB) by orchestrating CD8+ T cell activation and function. However, cDC1s often experience metabolic stress and exhibit decreased functional fitness within the tumor microenvironment. In this study, we aimed to identify key metabolic regulators that promote cDC1-dependent antitumor responses, which represent putative targets to metabolically engineer cDC1s to combat cancer, especially in combination with ICB therapy. RESULTS: We established, from both mouse and human tumors, that cDC1s exhibit discrete mitochondrial states. One subpopulation, referred to as [TMRM/MG]hi cells, contained polarized mitochondria, as demonstrated by the ratio of mitochondrial membrane potential [measured with tetramethylrhodamine methyl ester perchlorate (TMRM)] compared with mitochondrial mass [measured with MitoTracker Green (MG)]; whereas the other subpopulation, [TMRM/MG]lo cells, had depolarized mitochondria. Intratumoral cDC1s with polarized mitochondria more effectively primed CD8+ T cell responses than those with depolarized mitochondria. Using unbiased profiling approaches and experimental validations, we uncovered that OPA1 orchestrates the mitochondrial states and morphology in intratumoral cDC1s. Notably, OPA1 deletion in cDC1s led to increased tumor growth and impaired antitumor CD8+ T cell responses, corresponding to defective antigen presentation by cDC1s. Mechanistically, we established that OPA1 supports nuclear respiratory factor 1 (NRF1) activity and expression to sustain mitochondrial OXPHOS in cDC1s. OPA1-NRF1 axis–mediated OXPHOS inhibited autophagy and lysosome–dependent degradation of major histocompatibility complex I (MHC-I) and antigen. In addition, OPA1-mediated electron transport chain (ETC) flow contributed to cDC1 immunogenicity by facilitating NADH-to-NAD+ conversion (i.e., conversion from the reduced to the oxidized form of nicotinamide adenine dinucleotide). These OPA1-dependent effects were antagonized by mitochondrial fission protein DRP1. During tumor progression, intratumoral cDC1s experienced a progressive mitochondrial dysfunction, as revealed by reduction of the [TMRM/MG]hi subpopulation as well as decreased mitochondrial volume and OPA1-NRF1 signaling. Intratumoral administration of tumor antigen–pulsed cDC1s with polarized mitochondria into tumor-bearing mice resulted in superior tumor control compared with cDC1s with depolarized mitochondria, particularly when combined with ICB therapies. Indeed, a substantial proportion of mice receiving cotreatment of tumor antigen–pulsed cDC1s with polarized mitochondria plus ICB completely rejected tumors and developed durable immune memory responses upon tumor rechallenge. CONCLUSION: We uncovered discrete mitochondrial states and the underlying mitochondrial metabolic signaling programs in cDC1s that support their functional fitness in antitumor immunity and the establishment of durable ICB responses. These discoveries provide opportunities to reinvigorate cDC1s for improved cancer immunotherapy. Mitochondrial metabolism and signaling orchestrate cDC1 antitumor responses.: (Left) [TMRM/MG]hi cDC1s more effectively prime CD8+ T cell responses and control tumor growth compared with [TMRM/MG]lo cells. Intratumoral cDC1s undergo mitochondrial dysfunction and decreased OPA1-NRF1 signaling during tumor progression. (Right) The OPA1-NRF1 axis maintains OXPHOS to inhibit autophagy and lysosome–mediated degradation of MHC-I and antigen. OPA1-mediated ETC flow also supports cDC1 immunogenicity by balancing the NAD+/NADH ratio. These effects are antagonized by DRP1. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
|---|---|
| ISSN: | 00368075 |
| DOI: | 10.1126/science.adv6582 |
