Targeting mitochondrial metabolism to improve the tumor microenvironment: A bibliometric study and brief review (1994-2024)

doi:10.21203/rs.3.rs-4922171/v1

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Targeting mitochondrial metabolism to improve the tumor microenvironment: A bibliometric study and brief review (1994-2024)

https://doi.org/10.21203/rs.3.rs-4922171/v1

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Background

The tumor microenvironment (TME) plays a pivotal role in supporting tumor growth and metastasis via several inhibitory mechanisms, which diminish the effectiveness of cancer immunotherapy. Central to the metabolic reprogramming of tumors, mitochondria orchestrate the immunosuppressive landscape of the TME.

Methods

We extracted data spanning from 1994 to 2024 from the Web of Science Core Collection database, focusing on literature pertinent to this field. To maintain dataset consistency, we re-evaluated original research articles and compared them across various literature types.

Results

The study identified 3,947 publications, with original research articles comprising 67.29% (2,656 articles). The overall trend of publications increased from 2010 onwards, with a surge in publications from 2020. Cancers is the core journal with the most publications. Cell Metabolism has the most total citations and is the most influential journal. Among individual contributors, Zhang J has the highest number of publications, and Vander Heiden MG leads in local citations. Key figures such as Lisanti MP, Sotgia F, and Thompson CB are prominent authors. Thomas Jefferson University is noted for pioneering and sustaining research efforts, whereas Fudan University tops in publication volume. While China leads in publication quantity, the USA excels in total citations. The core literature encompasses studies on metabolic enzymes, oncogenes, the Warburg effect, and related themes.

Conclusion

The last three years have seen a burgeoning of interest in this field, with key areas such as gene expression, glycolysis, glutamine metabolism, and oxidative phosphorylation emerging as central themes.

Mitochondrial metabolism

Tumor microenvironment

Metabolic reprogramming

Bibliometric

Cancer immunotherapy

The tumor microenvironment (TME) comprises a sophisticated network of cellular and molecular interactions that facilitate tumor growth and metastasis through various mechanisms that enable tumors to evade immune surveillance^1,2. A notable characteristic of the TME is its enhanced immunosuppressive metabolism, where tumor cells thrive due to their metabolic adaptability, while immune cells suffer significant impairment³. Tumor cells consume large amounts of oxygen and nutrients to achieve rapid proliferation, coupled with a variety of factors such as vascular dysfunction, resulting in a hypoxic, acidic environment⁴. This adverse environment diminishes the effectiveness and quantity of CD8 T cells, making tumors resistant to immunotherapy and often resulting in poor patient outcomes^5,6. Mitochondria play a pivotal role as the powerhouses of cellular metabolism, especially in oxygen-depleted TME, by regulating bio-energy production and distribution⁷. This adaptation supports tumor cell proliferation and differentiation⁸.

Bibliometrics is a methodological approach that evaluates scholarly publications to perform statistical analysis and visualization of data⁹. It can effectively identify research hotspots and trends, providing insights into the connections among published works and enhancing understanding within specific fields. To date, various bibliometric studies have explored TME and mitochondrial metabolism, including the relationship between impaired mitochondrial metabolism and non-neoplastic diseases^10,11, the development of TME¹², and the effect of immunotherapy on TME¹³. However, there is a noticeable gap in bibliometric studies that integrate mitochondrial metabolism, TME, and tumor immunotherapy. Given the emerging potential of targeting mitochondrial metabolism in cancer treatments, conducting a systematic review to map out future research directions in this domain is deemed crucial¹⁴, we consider it necessary to conduct a systematic review and identify future trends in this area of research.

Data collection

Bibliographic data for this study were sourced from the Web of Science Core Collection database (WoSCC, Clarivate Analytics)^15,16, specifically including the Social Sciences Citation Index and the Science Citation Index Expanded editions. To eliminate bias from daily updates to the database, all searches through the WoSCC were conducted on a single day, May 12, 2024, covering publications from January 1, 1994, to May 12, 2024. The search strategy employed was [(TS=(((“mitochondrial metabolism”) OR (“oxidative phosphorylation”) OR (“OXPHOS”) OR (“tricarboxylic acid cycle”) OR (“TCA cycle”) OR (“β-oxidation”) OR (“fatty acid oxidation”) OR (“glutamine metabolism”) OR (“electron transport system”)) AND ((“tumor metabolism*”) OR (“cancer metabolism*”) OR (“metabolic reprogramming”) OR (“tumor microenvironment”) OR (“cancer microenvironment”) OR (“tumor immune microenvironment”) OR (“tumor immunosuppressive microenvironment”) OR (“TME”) OR (“immune checkpoint”) OR (“cancer immunotherapy*”) OR (“tumor immunotherapy*”))))]. The above keywords were curated from the Medical Subject Headings (MeSH) database (https://www.ncbi.nlm.nih.gov/mesh/). Filters were applied to select only 'articles' and 'reviews' as document types and 'English' as the document language. To ensure data consistency, we excluded review-type literature from our analysis, focusing solely on original-type articles, and compared these with the broader dataset of all literature types (Fig. 1A).

Data analysis

Data collection and preprocessing were carried out independently by two researchers. In cases where there was a disagreement regarding the classification of documents, a third researcher made the final decision. The biblioshiny website¹⁷ in the bibliometrix R-package was utilized to eliminate duplicates (n = 0), conduct frequency statistics, and generate plots. The data were organized into tables using Microsoft Excel (version 2304 Build 16.0.16327.20200). Information about the journals was obtained from the 2022 Journal Citation Report by Clarivate Analytics, Philadelphia, PA, USA. Keyword consolidation was performed using the thesaurus_terms.txt file in VOSviewer software. For bibliometric and visual analyzes following software were used: VOSviewer (version 1.6.19, van Eck and Waltman, 2010,^18,19), Origin (version 2022) and SCImago Graphica (version 1.0.26, Yusef Hassan-Montero, V. Guerrero-Bote, and Félix De-Moya-Anegón,^20,21). We have included visual analyses and data from original research articles in the main text to facilitate a precise understanding of the field. Additionally, literature of a review nature was placed in the Supplementary Material to provide a comprehensive overview for researchers.

General analysis of publication status

This study retrieved a total of 3,947 publications across various types, with 2,656 (67.29%) classified as ARTICLE-type publications. Given the substantial number of REVIEW-type articles, it was deemed necessary to analyze the ARTICLE-type literature separately. Examination of the total publication count revealed an increasing trend beginning in 2010, characterized by steady growth until 2019, followed by a marked rise starting in 2020, as illustrated in Fig. 1B. ARTICLE-type publications also increased from 2010, maintaining a relatively stable trend until experiencing rapid growth in 2020, which then plateaued in 2022 and 2023. In terms of citations, 2008 witnessed the highest average total citations per document among all types of publications, reaching 586.43 citations. This was followed by 2005 with 356 citations and 2002 with 350 citations, although these years did not see a high volume of publications, suggesting these were influenced by retrospective citation of literature. The year 2016 recorded the most citations overall at 25,430, with 2020 following at 21,368 citations. In the domain of original research literature, the average total citation trend was the same as overall, with the top three being 2008 (468.4), 2005 (356), and 2002 (350).

Analysis of journals and their influence

This study analyzed a total of 851 sources across all literature categories, with 662 (77.79%) of these being journal publications that featured original research. Among these, Cancers led with the highest number of publications at 173, followed by Frontiers in Oncology with 153 publications, and Frontiers in Immunology with 120 (Supplementary Fig. 1). Specifically focusing on journals publishing original research, Cancers remained in the top position with 92 publications, with Frontiers in Immunology at second with 69 publications, Scientific Reports third with 64 publications, and Frontiers in Oncology fourth with 63 publications. Bradford's Law was applied to determine the core journals in this field, identifying 22 journals as central to publishing original research, as depicted in Fig. 2A. In terms of citations within the field, Nature emerged as the most frequently cited journal, amassing 11,280 citations, followed by Cancer Research with 9,670 citations, and Cell with 9,269 citations. Within the context of journals featuring original research, Nature again led with 4,645 citations, Proceedings of The National Academy of Sciences of The United States of America came second with 3,984 citations, Cell third with 3,948 citations, and Cancer Research fourth with 3,833 citations. In terms of journal impact, the largest number of total citations was Cell Metabolism (9707), among which 56.44% (5479) were of original type. It was followed by Nature, which has 5,210 citations, with 88.83% (4628) of the original literature. The 3rd was Cell Cycle (5139) with 5,139 citations, and an impressive 99.81% (5,129 citations) of those are from original research articles The h-index, which measures the productivity and citation impact of the publications²², shows Oncotarget with the highest h-index at 36, where 94.44% (34) of the cited articles are original research. Other journals with notable h-indexes include Cell Cycle and Nature Communications, both with an h-index of 32 for original research articles. Cancer Research follows with an h-index of 30 for original articles, while Frontiers in Immunology and Frontiers in Oncology have h-indexes of 20 and 15, respectively, for original type. Table 1 shows the local impact data for journals publishing original research to clearly depict their academic influence and standing within the field.

Table 1

Top 10 core journals and their impact
Rank	Journal	Total citations	Article count	H-index	G-index	Journal citation reports(2022)	Impact factor(2022)
1	Cancers	907	92	17	23	Q2	5.2
2	Frontiers In Immunology	1168	69	20	33	Q1	7.3
3	Scientific Reports	1864	64	23	42	Q2	4.6
4	Frontiers In Oncology	593	63	15	21	Q2	4.7
5	Oncotarget	2897	58	34	53	\	\
6	Nature Communications	3978	45	32	45	Q1	16.6
7	Cancer Research	3845	45	30	45	Q1	11.2
8	Cell Reports	2962	41	27	41	Q1	8.8
9	Cell Death & Disease	1368	37	19	36	Q2	9
10	Plos One	1239	37	21	35	Q2	3.7

According to the analysis of the top 22 journals ranked by annual publication numbers (Fig. 2B), Cell Cycle led in 2012 with a total of 13 articles, all classified as ARTICLE-type. Oncotarget recorded the highest number of articles in 2016, totaling 23, with 21 being original-type articles. However, it did not maintain this trend beyond 2017. Cancers experienced a notable increase in publications, reaching 36 in 2020, and then stabilizing at 45 in both 2021 and 2022, with the peak for original-type articles occurring in 2021 with 30 publications. Similarly, Frontiers in Oncology also published 45 articles in 2022, among which 25 were original-type articles. The highest publication count in 2023 was seen in Frontiers in Immunology, which published 32 articles, with 20 of these being original research articles.

Analysis of authors and their production

The study included 21,543 authors across all types of literature, with 18,505 of these contributing to original-type literature. In the complete dataset, Zhang J led with the highest number of publications at 46, followed by Wang Y with 40 publications, and another Zhang J with 39. Both Lisanti MP and Sotgia F published 38 articles each. In terms of publication trends among the top 15 authors, Lisanti MP, Sotgia F, and Martine-Outschoorn UE were most prolific in 2011 and 2022. Among the authors who published primary literature, Zhang J again topped the list with 36 publications, followed by Li J and Lisanti MP, each with 33 publications, and Liu Y and Sotgia F, both with 32 publications. Table 2 depicts the impact data of the top 10 authors who published primary literature. Figure 3A shows the distribution of the top 20 authors by country, with China and the USA leading significantly ahead of other nations. Regarding institutions, Thomas Jefferson University had the highest number of publications, followed by Fudan University, Sun Yat-sen University, and the University of Texas MD Anderson Cancer Center. Additionally, Fig. 3B illustrates the publication trends of the top 15 authors. Notably, Lisanti MP, Sotgia F, Martine-Outschoorn UE, and Howell A had their peak publication years in 2011 and 2012.

Table 2

Top 10 core authors and their influence
Rank	Author	Article count	h_index	g_index	Total citations	Publication Start Year
1	Lisanti MP	33	32	33	5153	2009
2	Sotgia F	32	32	32	5132	2009
3	Cantley LC	8	6	8	4849	2008
4	Martinez-Outschoorn UE	26	26	26	4473	2009
5	Whitaker-Menezes D	25	23	25	4114	2009
6	Pestell RG	20	20	20	4085	2009
7	Vander Heiden MG	8	7	8	3662	2008
8	Howell A	24	24	24	3518	2010
9	Thompson CB	5	5	5	3391	2011
10	Ward PS	2	2	2	3078	2011

Regarding citation metrics, several authors have achieved significant recognition in the field based on local citations across all types of literature, with Vander Heiden MG (1,053 citations), Lisanti MP (1,042 citations), Sotgia F (1,040 citations), and Thompson CB (1,001 citations) being central figures due to their extensive citations (Supplementary Fig. 2). For published primary literature, the most locally cited authors are Lisanti MP with 456 citations, followed closely by Sotgia F with 454 citations, and Martinez-Outschoorn UE with 407 citations. In terms of total citations from all published works, Vander Heiden MG leads with 9,102 citations and an h-index of 14. Thompson CB is second with 7,815 citations and an h-index of 9, while Deberardinis RJ holds third place with 6,392 citations and the highest h-index among them at 18. Meanwhile, the highest h-index was found in Sotgia F (36), followed by Lisanti MP. Moreover, the difference in total citations between the two was not much, both were around 6000. In contrast, when focusing on original literature, Lisanti MP topped the list with 5,153 total citations and an h-index of 32, Sotgia F followed with 5,132 citations and an h-index of 32, and Cantley LC ranked third in citations with 4,849, but has a lower h-index at 6. Additionally, Martinez-Outschoorn UE ranked third in terms of h-index among authors of original literature, at 26.

Analysis of institutions, countries/regions, and their cooperation

Among all the institutions contributing to the literature in this field, Fudan University led with 191 publications, closely followed by Thomas Jefferson University with 188 publications, and the University of Texas MD Anderson Cancer Center with 167 publications. These institutions are prominently active in research. Specifically, Thomas Jefferson University was an early contributor, experiencing a significant surge in publications during 2011–2012, followed by a steady increase. Fudan University has shown a notable rise in publications from 2020 to 2023. When examining only the original type of literature, the ranking shifts slightly: Thomas Jefferson University held the top position with 163 publications, followed by the University of Texas MD Anderson Cancer Center with 146 publications, and Fudan University with 144 publications, as depicted in Fig. 4A. Regarding institutional collaborations, the analysis highlights prominent networks: one included Fudan University, Shanghai Jiaotong University, and Sun Yat-sen University; another featured Harvard Medical School, the University of Texas MD Anderson Cancer Center, and the University of Pennsylvania; and a third core team comprised of Thomas Jefferson University and The University of Manchester, as shown in Fig. 4B.

In terms of publication volume by country, China led with a total of 1,243 articles, closely followed by the USA with 1,081 articles. The gap between these two leaders and other countries was found to be significant. However, when looking at citations, the USA far outpaced China with 95,951 total citations compared to China's 26,630, with the United Kingdom (8,859 citations) and Italy (8,339 citations) ranked third and fourth, respectively. Focusing on original types of literature, the USA led in scientific output with 4,139 publications, while China followed closely with 3,670 publications. This shows that while China is slightly behind the USA in the number of publications, the competition between the two is intense (Fig. 4C ~ D). Regarding the countries of corresponding authors, China again had the highest number of articles at 895, with the USA second at 754, both far ahead of other countries. In terms of citations among corresponding author countries, the USA remained dominant with 56,740 citations, significantly ahead of China's 16,198 citations. The United Kingdom and Italy maintained their third and fourth positions with 4,576 and 4,163 citations, respectively. Notably, the average citation rate per article for the USA stood at 75.25, while the United Kingdom, ranked third, has an average citation rate of 70.40.

Analysis of keywords

In this study, we conducted a comprehensive comparison of keywords across all types of literature and specifically within original-type literature. The top ten keywords identified were: gene expression, metabolism, cancer, glycolysis, cancer metabolism, glutamine metabolism, oxidative phosphorylation (OXPHOS), tumor growth, cell, and mitochondria. The keyword clustering for original-type literature (Fig. 5A) categorizes the field into four main thematic areas: (1) tumor hallmarks, progression, drug resistance, treatment options, and the dynamics within the TME; (2) metabolic reprogramming, gene expression, and associated activation mechanisms; (3) studies on mitochondrial metabolism, autophagy, and oxidative stress; and (4) the impact of hypoxic environments on cancer metabolism and its metabolites. The keyword trend analysis spanning from 2011 to 2024 (Fig. 5B) shows that research on mitochondria-related topics like the respiratory chain, OXPHOS, and reactive oxygen species (ROS) has been sustained over a long period. More recently, in the past three years, topics such as cuproptosis and ferroptosis have emerged as new areas of interest. Figure 5C indicates that topics like macrophage polarization, glutamine metabolism, and OXPHOS are considered niche areas, while foundational topics revolve around gene expression and mitochondrial stimulation in tumor cells. The clustering distribution of all types of literature is illustrated in the supplementary Fig. 3. The word map analysis (Fig. 5D) underscores these themes and highlights other areas requiring further attention, such as apoptosis, stem cells, and fatty acid oxidation. Our discussion section includes a systematic review of these core keywords and emerging trends, hoping to help researchers understand the depth and potential of the field.

Analysis of documents/references

We initiated our investigation by examining the most globally cited works (Table 3, Supplementary Table 1). Leading the citation count, the review "The Emerging Hallmarks of Cancer Metabolism" by Natalya N. Pavlova et al., published in Cell Metabolism in 2016, garnered a total of 3,499 citations²³. This seminal review categorizes cancer-associated metabolic patterns into six hallmarks, thoroughly discussed as follows: (1) deregulated uptake of glucose and amino acids; (2) opportunistic modes of nutrient acquisition; (3) utilization of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production; (4) heightened nitrogen demand; (5) metabolite-driven gene regulation; and (6) metabolic interactions with the microenvironment. Our current study focuses on the sixth hallmark, exploring the role of mitochondria in the nexus between cancer metabolism and the TME. The second most cited publication by total citations was Patrick S Ward et al published in Cancer Cell in 2012 titled Metabolic reprogramming: a cancer hallmark even warburg did not anticipate²⁴. This paper differentiates the mitochondria in quiescent versus proliferating cells and elaborates on the influence of the PI3K/Akt/mTORC1 pathway, HIF-1, and Myc activation in mitochondrial metabolic reprogramming, which promotes tumor progression. It further discusses the role of metabolic enzymes and metabolites as oncogenes, underlining the pivotal role of metabolic alterations in cancer. The previous 2 articles are also the top 2 locally cited documents.

Table 3

Top10 most-cited global documents
Rank	Title	First Author	Year	Journal	Total Citations	DOI
1	The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth	Christofk HR	2008	Nature	2141	10.1038/nature06734
2	The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation	Wang RN	2011	Immunity	1475	10.1016/j.immuni.2011.09.021
3	Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway	Son J	2013	Nature	1413	10.1038/nature12040
4	Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages	Mills EL	2016	Cell	1250	10.1016/j.cell.2016.08.064
5	The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma	Pavlides S	2009	Cell Cycle	1019	10.4161/cc.8.23.10238
6	Cancer metabolism: fatty acid oxidation in the limelight	Carracedo A	2013	Nature Reviews Cancer	888	10.1038/nrc3483
7	Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells	Le A	2012	Cell Metabolism	834	10.1016/j.cmet.2011.12.009
8	Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages	Ip Wke	2017	Science	792	10.1126/science.aal3535
9	PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation	Patsoukis N	2015	Nature Communications	762	10.1038/ncomms7692
10	Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry	Hirayama A	2009	Cancer Research	760	10.1158/0008-5472.CAN-08-4806

The review article From Krebs to clinic: glutamine metabolism to cancer therapy by Brian J Altman et al published in Nature Reviews Cancer in 2016 is the 3rd local highly cited article²⁵. This article extensively covers the basic processes of glutamine metabolism, its metabolizing enzymes, and the clinical treatments emerging from this understanding, along with future prospects. In addition, the overall citations for the original type article The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth by Heather R Christofk et al published in Nature in 2008 are also high (2141) ²⁶. This original study suggests that shifting tumor cells from the embryonic M2 isoform of pyruvate kinase to the M1 isoform could counteract the Warburg effect. The original paper The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation published by Ruoning Wang et al in 2011 in Immunity is also highly cited²⁷. This study places the transcription factor Myc at the forefront, highlighting its role in activating glutamine metabolism and driving T-cell activation through metabolic reprogramming. The original study by Jaekyoung Son et al. published in Nature in 2013 Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway also garnered great citations²⁸. Their study centered on in-depth in-vivo and in-vitro experiments related to glutamine metabolism, and highlighted the critical role of the oncogene KRAS in glutamine metabolism. Table 4 and Supplementary Table 2 depict the most cited references for local documents.

Table 4

Top10 most-cited local references
Rank	Title	First Author	Year	Journal	Citations	DOI
1	Understanding the Warburg effect: the metabolic requirements of cell proliferation	Heiden Mgv	2009	Science	475	10.1126/SCIENCE.1160809
2	Hallmarks of cancer: the next generation	Hanahan D	2011	Cell	376	10.1016/J.CELL.2011.02.013
3	On the origin of cancer cells	Warburg O	1956	Science	326	10.1126/SCIENCE.123.3191.309
4	The Emerging Hallmarks of Cancer Metabolism	Pavlova NN	2016	Cell Metabolism	205	10.1016/J.CMET.2015.12.006
5	Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis	Deberardinis RJ	2007	Proceedings of The National Academy of Sciences of The United States of America	198	10.1073/PNAS.0709747104
6	The biology of cancer: metabolic reprogramming fuels cell growth and proliferation	Deberardinis RJ	2008	Cell Metabolism	151	10.1016/J.CMET.2007.10.002
7	Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles	Subramanian A	2005	Proceedings of The National Academy of Sciences of The United States of America	147	10.1073/PNAS.0506580102
8	Metabolic reprogramming: a cancer hallmark even warburg did not anticipate	Ward PS	2012	Cancer Cell	145	10.1016/J.CCR.2012.02.014
9	Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction	Wise DR	2008	Proceedings of The National Academy of Sciences of The United States of America	140	10.1073/PNAS.0810199105
10	From Krebs to clinic: glutamine metabolism to cancer therapy	Altman BJ	2016	Nature Reviews Cancer	131	10.1038/NRC.2016.71

1 Mitochondrial structure and function

Mitochondria originated from a significant endosymbiotic event where a eukaryotic ancestor engulfed an alpha-proteobacterium²⁹. It consists of outer membranes (OM), inner membranes (IM), intermembrane space (IMS), and matrix compartments³⁰. As central regulators of metabolism in organisms, mitochondria play a critical role in global energy production, oxidative reactions, and various cellular functions such as the generation of ROS, regulation of cytoplasmic Ca²⁺, and others⁸. Additionally, their dynamic behaviors, including fusion, fission, transport, and mitophagy, are closely linked to their metabolic functions³¹. OXPHOS, tricarboxylic acid (TCA) cycle, electron transport system (ETS), and fatty acid oxidation (FAO) are the core functional manifestations of mitochondrial metabolism. Mitochondria oxidize glucose, fatty acids, and amino acids to release energy, fulfilling cellular energy requirements³². Glucose is produced through glycolysis to produce pyruvate, which enters the mitochondria via the mitochondrial pyruvate carrier. In the mitochondria, pyruvate is converted to acetyl-coenzyme A (Acetyl-CoA) by pyruvate dehydrogenase. This Acetyl-CoA then feeds into the TCA cycle, where it is further broken down. The high-energy electrons produced from this cycle are transferred to the electron transport chain (ETC) at the IM, pumping electrons from the mitochondrial matrix to the IMS and creating an electrochemical gradient. This gradient drive ATPase to phosphorylate ADP into ATP, providing the cell with energy³³. Fatty acids then enter the cell and are converted to fatty acyl-coenzyme A (fatty acyl-CoA), which is converted to fatty acyl-carnitines by mitochondrial membrane-bound carnitine palmitoyl transferase 1 (CPT1) for translocation into the mitochondria, reconverted to acyl-CoA by CPT2, and further oxidized to form Acetyl-CoA to participate in the TCA cycle³⁴. The nonessential amino acid glutamine serves as a vital carbon source for tumor cells, converted into succinyl-coenzyme A and Acetyl-CoA through the α-ketoacid dehydrogenase complex, and then utilized in the TCA cycle within mitochondria³⁵. A thorough understanding of mitochondrial structure and function is crucial for identifying its potential role in tumor diagnosis and therapy.

2 Metabolic reprogramming and mitochondrial metabolism

Currently, the study of cancer metabolism is a primary focus for investigating tumor development mechanisms, creating therapeutic approaches, and addressing drug resistance, with mitochondria presenting a significant challenge^36,37. A fundamental characteristic of cancer is its metabolic reprogramming, which adjusts energy metabolism patterns to support cell growth and proliferation³⁸. In the 1920s, Otto Warburg and his colleagues initially proposed that cancer cells exhibit an altered metabolic state³⁹. They observed that cancer cells consume large amounts of glucose and primarily perform aerobic glycolysis, a process now known as the "Warburg effect," where glucose is converted to lactic acid even in the presence of sufficient oxygen⁴⁰. In this case, the mitochondrial responsible process of OXPHOS is decoupled. In subsequent studies, Otto Warburg also proposed that it was dysfunctional mitochondria that primarily mediated aerobic glycolysis⁴¹. The Warburg effect is recognized for giving tumors a growth advantage, although it understates the role of mitochondria in cancer. Interestingly, recent studies have indicated that the Warburg effect and mitochondrial metabolism actually share an integrated system, with tumor cells undergoing both aerobic glycolysis and mitochondrial respiration, reflecting the metabolic plasticity in the TME^42,43. And it has been suggested that targeting mitochondrial metabolism may be even more necessary in tumor therapy than dismantling the Warburg effect⁴⁴. Contemporary theories suggest that increased mitochondrial activity might overload its metabolic capacity, leading to the Warburg effect⁴⁵, however, the underlying molecular mechanisms require further investigation. In addition, other forms of metabolic reprogramming in cancer include increasing FAO to promote tumor chemoresistance⁴⁶ and upregulating glutamine metabolism to promote tumor growth⁴⁷.

3 Mitochondrial oxidative stress and tumor antioxidation

Oxidative stress is a critical link in the interplay between mitochondrial metabolism and TME⁴⁸. Although cancer oxidative stress includes various elements such as mitochondrial stress, endoplasmic reticulum stress, and oxidative damage to DNA, mitochondria are central to this process due to their significant ROS production. During mitochondrial respiration, most electrons travel along the ETC and ultimately combine with molecular oxygen to form water. However, a fraction of these electrons may escape from Complex I and III of the ETC, leading to the production of ROS⁴⁹. In the hypoxic conditions of the TME, mitochondrial ROS levels are heightened, causing oxidative stress that can induce autophagy, apoptosis, and cell death. ROS are capable of triggering mitochondrial signaling mechanisms, such as the activation of the mitochondrial permeability transition pore (mPTP), which can lead to necrotic cell death ⁵⁰. Meanwhile, ROS can activate a variety of classical signaling pathways, such as the NF-κB⁵¹, PI3K/Akt⁵², and JNK/AP-1⁵³ pathways. The tumor suppressor, p53, can also be activated by direct oxidation of ROS, which in turn triggers cell cycle arrest, apoptosis, etc^54,55. However, tumor cells often undergo metabolic reprogramming to eliminate ROS, which contributes to tumor resistance, progression, and recurrence ^56,57. Tumor-protective antioxidant pathways include activation of oncogenes KRAS, BRAF, MYC, and MYC-directed nuclear factor erythroid 2-related factor 2 (NRF2)^58–60. In hypoxic tumor conditions, hypoxia-inducible factors (HIFs) are also activated, which are intricately connected to mitochondrial respiratory activity and ROS production⁶¹, and they interact with NRF2 signaling, linking the key tumor characteristics of hypoxia and oxidative stress⁶². Moreover, Nicotinamide adenine dinucleotide phosphate (NADPH) plays a crucial role in this defensive system by helping maintain reduced glutathione and thioredoxin⁶³. Concomitantly, NADPH oxidase 4 (NOX4) is gaining attention as a potential tumor-suppressive target^64,65. The potential of this area for anti-tumor targeting warrants further in-depth exploration.

4 Mitochondrial metabolic reprogramming and antitumor immunity

Mitochondria significantly enhance the metabolic adaptability of tumors, enabling cancer cells to sustain growth and survival by adapting to the dynamic changes in their microenvironment. In addition, a prior study integrating extensive single-cell RNA sequencing suggested that mitochondrial activity is crucial in fostering metabolic diversity within tumors, with OXPHOS and the TCA cycle playing key roles⁶⁶. The OXPHOS pathway has also been found to be enriched in malignant melanoma brain metastases⁶⁷. Consequently, researchers have suggested targeting the OXPHOS process as a therapeutic strategy in cancer treatment, leveraging the reliance of various cancer types on this pathway^68,69. By modifying mitochondrial activity and the cellular metabolic state can influence cell fate and regulate overall cellular functions⁷⁰. It has been suggested that OXPHOS inhibition can decrease tumor oxygen consumption, enhance oxygen availability, and stimulate the immune response, potentially boosting the effectiveness of antitumor therapy^71,72. Based on the therapeutic strategy of the inhibition of the ETC to reduce mitochondrial respiratory production, OXPHOS inhibitors have emerged. Their combination with chemotherapy, radiotherapy, and immunotherapy has been reported to circumvent PD-1 resistance and produce synergistic antitumor effects^73,74. Furthermore, tumors with increased glutamine uptake can suppress the TME, facilitating immune evasion, as indicated by the elevated levels of immune checkpoints like PD-1, PD-L1, and regulatory T cells (Tregs)⁷⁵. Altering glutamine metabolism in cancer cells not only deprives them but also supports glutamine availability for immune cells, enhancing the effectiveness of treatments such as PD-L1 antibodies, particularly in triple-negative breast cancer⁷⁶. Additionally, various metabolic enzymes and metabolites, through metabolic reprogramming, exhibit unconventional roles like epigenetic modifications, gene transcription regulation, and cell fate determination. These roles, termed "Moonlighting functions"^77,78,are crucial in promoting malignant transformation and participating in cancer immunity, positioning these molecules as promising targets for current clinical therapies^79,80.

5 Mitochondrial metabolic reprogramming of T cells in TME

Metabolic reprogramming profoundly impacts various elements of the TME, including the activation and suppression of immune cells, their metabolic adaptation, and the activation of immune checkpoints. Metabolic reprogramming of tumor cells severely affects multiple components of the TME, including immune cell activation and suppression, immune cell metabolic remodeling, and immune checkpoint activation. Not only do tumor cells undergo metabolic reprogramming, but multiple immune effector and immunosuppressive cells in the TME also undergo this process^81,82. Naive T cells primarily rely on OXPHOS, crucial for their activation. Following antigen stimulation, T cells shift towards aerobic glycolysis to enhance their effector function, notably through the production of IFN-γ⁸³. However, in the TME, T cells face nutrient scarcity, leading to reduced aerobic glycolysis and subsequent inhibition of IFN-γ secretion and this can be partially reversed by glucose supplementation. Additionally, changes in metabolic phenotype are linked to PD-1 expression on CD4 T cells, and a high OXPHOS phenotype in CD8 T cells of melanoma patients was also closely associated with immune checkpoint inhibitor resistance⁸⁴. Furthermore, Coenzyme A enhances OXPHOS, promoting the polarization of CD8 T cells into Tc22 cells and enhancing the sensitivity of anti-PD-L1 immunotherapy and this metabolic reprogramming also sensitizes anti-PD-L1 immunotherapy⁸⁵. Several key molecules have been found to intervene in T cell metabolic reprogramming. Among them, sirtuins are considered to be core regulators of T-cell metabolism⁸⁶. Inhibiting sirtuin-2 can increase glycolysis and TCA cycling, thus boosting T cell activation, maturation, and the effectiveness of tumor immunotherapy⁸⁷. SUMO-specific protease 7 (SENP7), an oxidative stress receptor, can promote both glycolysis and OXPHOS in CD8 T cells, whereas its down-regulation can effectively inhibit the antitumor capacity of T cells⁸⁸. Moreover, the metabolic reprogramming of antigen-presenting cells like monocytes, which differentiate into dendritic cells (DCs), involves a transition from high to low glycolysis (from 82–14%) and low to high mitochondria-dependence (from 18–86%)⁸⁹. However, clinical trials in advanced melanoma patients receiving a DC vaccine indicated that increased glycolysis and reduced mitochondrial metabolism in DCs were associated with poorer outcomes⁹⁰ .

6 Mitochondrial metabolic reprogramming and tumor-associated macrophage polarization

Mitochondrial metabolism plays a crucial role in the polarization of tumor-associated macrophages (TAMs), which are integral to the TME, making up 30%-50% of its cellular composition and predominantly existing as leukocytes⁹¹. TAMs are generally categorized into two types: the anti-tumor, pro-inflammatory M1-type, and the pro-tumor, anti-inflammatory M2-type, with the latter being more prevalent and associated with poor tumor prognosis^92,93. TAMs exhibit considerable plasticity, meaning their polarization is not a fixed state, presenting an opportunity to target their polarization as a therapeutic strategy⁹⁴. In TMEs, the activation of HIF-1α induces an increase toward the M2 type of TAMs polarization⁹⁵. Conversely, promoting M1-type polarization has been shown to improve the immunosuppressive landscape of the TME, thereby enhancing the body's anti-tumor responses and the effectiveness of tumor immunotherapy⁹⁶. The metabolic activities of M1 and M2 TAMs are distinctly different, which are mainly manifested by their different oxygen consumption and dependence on mitochondrial metabolism⁹⁷. M1-type TAMs rely heavily on glycolysis for energy, producing nitric oxide (NO) and ROS, and exhibit a disrupted TCA cycle. On the other hand, M2-type TAMs depend significantly on mitochondrial respiration, maintain a complete TCA cycle, and primarily engage in OXPHOS and FAO. Moreover, M2-TAMs have limited glycolytic activity and predominantly express high levels of Arginase-1⁹⁸. Interestingly, elevated mitochondrial OXPHOS in M2-type TAMs can lead to increased ROS production, which may result in mitochondrial DNA (mtDNA) release. This release can activate the cGAS-STING signaling pathway, promoting a shift towards M1-type TAM polarization ^99,100. Given this metabolic variability between M1 and M2 TAMs, targeting their metabolic states has emerged as a promising anticancer therapy^101,102. Strategies to inhibit OXPHOS and FAO while boosting glycolysis could promote M1-type activation and suppress M2-type TAM functions, offering a novel approach to cancer treatment¹⁰³.

7 Therapeutic potential and trends in targeting mitochondria

Mitochondrial metabolism has become significantly influential in medical oncology, especially in enhancing tumor immunotherapy by targeting mitochondrial functions. Current research includes the development of mitochondria-targeted small molecule compounds, bioactive molecules, nanomaterials, and antioxidants. Notably, Metformin, originally a mitochondrial complex I inhibitor for treating type 2 diabetes, has garnered interest for its potential anticancer properties^104,105. A meta-analysis showed that Metformin may serve as an effective adjunct in treating colorectal and prostate cancers¹⁰⁶. A number of in-vivo and in-vitro experiments have found that metformin can enhance the therapeutic efficacy of tumor vaccines and immune checkpoint inhibitors including PD-1 and PD-L1^107,108. A phase II clinical trial explored the role of Metformin in combination with nivolumab in the treatment of patients with metastatic microsatellite stable colorectal cancer, noting increased T-cell infiltration in tumors, although not significantly impacting overall efficacy¹⁰⁹. An emerging innovative approach involves mitochondrial transplantation¹¹⁰, where transferring activated mitochondria to tumor cells promotes cell death via oxidative stress and autophagy ¹¹¹, demonstrating antitumor potential in as cholangiocarcinoma and breast cancer^112,113. Mitochondria are also being considered as "Living Drugs" through Artificial Mitochondrial Transfer/Transplant (AMT/T) to rejuvenate damaged cells and restore function, with ongoing research in genetic mitochondrial disorders, ischemia-reperfusion injuries, and skin aging^114–116. Additionally, mitochondria-targeted drug delivery systems are a focal point of research, employing nanocarriers to modify or encapsulate drugs directly. For instance, ROS-responsive nanoparticles targeted at mitochondria are under investigation to enhance mitochondrial oxidative stress, thereby promoting immunogenic death of tumor cells¹¹⁷. Similarly, mitochondria-targeted liposome nanoparticles in conjunction with ultrasound activation have also shown effective activation of anti-tumor immunity and synergistic enhancement of the effect of treatment in conjunction with PD-L1 antibodies¹¹⁸. Photodynamic therapy (PDT), using laser-induced ROS generation and nanoparticles equipped with mitochondrial metabolism inhibitors, has been effective in reversing the hypoxic tumor microenvironment, improving treatment outcomes^119,120. This ongoing exploration is expected to yield new strategies and methodologies for future tumor therapies.

Limitation

In this study, we examined the influence of mitochondrial metabolism on the tumor immune microenvironment and cancer immunotherapy. However, the study is subject to several limitations: (1) Scope limitations: the study primarily focuses on mitochondrial metabolism as a singular pathway and overlooks the potential roles of mitochondrial quality control mechanisms such as mitochondrial dynamics and autophagy in tumor immunity, which may significantly affect tumor progression and treatment outcomes. (2) Omission of metal ion transport: the study does not consider the transport of crucial metal ions like copper and iron, nor the cell death resulting from abnormal metal ion transport, including cuproptosis and ferroptosis. These aspects are critical to tumor immunity as well. (3) Generalized discussion: the analysis provided is somewhat broad and lacks detailed exploration of specific topics. Consequently, the paper offers a general overview rather than delivering detailed, nuanced insights. (4) Future research directions: while the paper proposes potential future research avenues, it does not delve into these areas comprehensively. Further studies could expand on these suggestions to gain a deeper understanding of tumor immune mechanisms. Moreover, although this study excluded review articles and re-evaluated original research articles to maintain accuracy and objectivity, it recognizes the value of review articles. As evidenced by the cited literature, review articles furnish essential background information, theoretical frameworks, and insight into research trends, which are vital for grasping the broader context of the research field.

In conclusion, this study employed bibliometric analysis to extract and visualize data from literature concerning mitochondrial metabolism, the tumor microenvironment, and cancer immunotherapy. By juxtaposing the data analysis from all reviewed literature against that from original research, a clearer understanding of the depth and trends within this field emerges. Notably, significant development has been observed since 2010, with a marked increase in activity over the past three years. Key terms identified in the field include gene expression, glycolysis, glutamine metabolism, and oxidative phosphorylation. Additionally, this study offers a detailed systematic review based on the identified keywords and pivotal publications/references, aiming to equip researchers and readers with essential insights and delineate the boundaries of current research in this area.

TME tumor microenvironment

OXPHOS oxidative phosphorylation

OM outer membranes

IM inner membranes

IMS intermembrane space

TCA tricarboxylic acid

ETS electron transport system

FAO fatty acid oxidation

Acetyl-CoA acetyl-coenzyme A

ETC electron transport chain

CPT1 carnitine palmitoyl transferase 1

mPTP mitochondrial permeability transition pore

NRF2 nuclear factor erythroid 2-related factor 2

HIFs hypoxia-inducible factors

NADPH Nicotinamide adenine dinucleotide phosphate

NOX4 NADPH oxidase 4

Tregs regulatory T cells

SENP7 SUMO-specific protease 7

DCs dendritic cells

TAMs tumor-associated macrophages

NO nitric oxide

mtDNA mitochondrial DNA

AMT/T Artificial Mitochondrial Transfer/Transplant

PDT Photodynamic therapy

Acknowledgements

The authors express their gratitude to the following software tools: Microsoft Excel, VOSviewer, R and the Scimago Graphica.

Authors' contributions

Conceptualization, Huilan Zheng; Formal Analysis, Huilan Zheng; Data Curation, Gang Wang, Jingping Wu and Huilan Zheng; Writing – Original Draft Preparation, Huilan Zheng; Writing – Review & Editing, Ming Liu and Huilan Zheng; Supervision, Hongbin Cheng and Ming Liu. All authors contributed to the article and approved the submitted version.

Funding

This research was supported by Sichuan Provincial Administration of Traditional Chinese Medicine (grant numbers 2023zd019). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability statement

The data supporting the conclusions of this article are included within the article and its additional files.

Declaration of interests

The authors declare no competing interests.

Declaration of generative AI and AI-assisted technologies in the writing process

None.

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Targeting mitochondrial metabolism to improve the tumor microenvironment: A bibliometric study and brief review (1994-2024)

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Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Method

Data collection

Data analysis

Results

General analysis of publication status

Analysis of journals and their influence

Analysis of authors and their production

Analysis of institutions, countries/regions, and their cooperation

Analysis of keywords

Analysis of documents/references

Discussion

1 Mitochondrial structure and function

2 Metabolic reprogramming and mitochondrial metabolism

3 Mitochondrial oxidative stress and tumor antioxidation

4 Mitochondrial metabolic reprogramming and antitumor immunity

5 Mitochondrial metabolic reprogramming of T cells in TME

6 Mitochondrial metabolic reprogramming and tumor-associated macrophage polarization

7 Therapeutic potential and trends in targeting mitochondria

Limitation

Conclusion

Abbreviations

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References

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