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本文选自2023年9月22日的《科学》杂志，所作分析仅为作者按照文章理解得出，如有错误和不当之处请指出，如有冒犯之处，请留言与本人协商。
metabolic control of antitumor immunity
Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation
研究基础：让细胞杀死细胞（提高免疫细胞的识别率，鉴别出癌细胞并将其杀死）
The metabolism（在生物医学领域，词根词缀得到了充分利用）of cancer cells adapts to meet an increased need for the energy, biosynthesis, and antioxidants required for proliferation, tumor growth, and metastasis. Yet, whether this metabolic reprogramming（总结第一句话）affects the recognition and elimination of cancer cells by immune cells has not been well investigated. （提出问题：代谢功能的重编是否会影响免疫细胞对癌细胞的识别和灭除）Mangalhara et al. report a connection between a cancer cell’s mitochondrialmetabolism and its ability to evoke an immune response in a mouse model of melanoma. （点题：癌细胞线粒体的代谢诱发免疫应答）（发现，关键词：动物实验，癌症相关，免疫治疗相关，黑色素瘤）（下面是具体发现（生化过程）和原理：）Specific perturbations of the mitochondrial electron transport chain increased succinate production in cancer cells. Succinate accumulation caused epigenetic rearrangements, which induced the expression of genes involved in antigen presentation. This promoted the detection of tumor cells by surveilling T cells – tumor immunogenicity（研究发现的作用）.（以上为原理）The identification of a mechanism by which mitochondrialmetabolites shape tumor immunogenicity has potential for developing anticancer therapies. （研究发现的应用）（mitochondrial metabolites shape tumor immunogenicity全文关键）
The adaptive immune system comprises cells that recognize and response to various external stimuli through a process called antigen presentation. During the early stages of tumor development, cytotoxic immune cells, such as CD8+ T cells, recognize and eliminate immunogenic cancer cells, preventing tumor growth and metastasis. However, as they progress, tumors often acquire properties that allow them to escape immune detection. （以上为肿瘤细胞escape免疫检测的生化过程）metabolism of immune cells is an important determinant of their function, including anticancer immunity. （通过上述生化过程，得出解决问题（抗癌免疫）的关键）But whether metabolism in cancer cells affects their immunogenicity has been an open question. （但是问题并未解决）Mangalhara et al. assessed the role of complex I (CI) and complex II (CII) of the mitochondrial electron transport chain on melanoma growth. Pharmacological inhibition or genetic ablation of CII in mice enhanced the antitumor immune response by increasing antigen presentation by melanoma cells. This blocked tumor growth. （生化过程，第一段结尾从理论上解释了Mangalhara等人研究发现的应用，这里具体说明了小鼠实验的生化过程：对小鼠的CII进行药物抑制或基因消融后，黑色素瘤细胞的抗原呈递会增加，从而增强抗肿瘤免疫应答，遏制肿瘤生长。）
How is CII inhibition in cancer cells connected to the antitumor immune response? （让想到这个问题的读者产生共鸣，让没有想到这个问题的读者感兴趣）（讲道理，回答问题：）metabolism is tightly linked to epigenetics; various metabolites act as substrates or cofactors for DNA- and histone-modifying enzymes that regulate the chromatin landscape and thus, gene expression.（关键）For example, α-ketoglutarate, which is produced in mitochondria as part of the tricarboxylic acid cycle, is required for the activity of histone demethylases. The function of these enzymes is also regulated by competitive inhibitors, most of which are tricarboxylic acid cycle intermediates, such as succinate. （以上为前辈的发现，下文为根据这些发现，Mangalhara的发现）
Mangalhara et al. demonstrate that in tumor cells succinate accumulation resulting from （生化过程推进词汇）CII inhibition decreased the α-ketoglutarate/succinate ratio, which subsequentlyinhibited histone demethylases. The inhibition ofthese epigenetic enzymes increased the trimethylation of histone 3 lysine4 (H3K4) and H3K36 on genes involved in（生化过程推进词汇） antigen processing and presentation, which induced the expression of these genes and activated T cell-mediated killing of tumor cells. These changes were reversed by the addition of α-ketoglutarate,which reactivates histone demethylases. （一步一步说明，which在语法上虽然是关系代词，在说明生化现象时却是步步递进，将生化过程不断向前推进的重要标志词汇。these等指代词汇具备同样功能）
Mangalhara 等人对于发现中存在的问题，提出的解决办法：The systemic inhibition of CII activity is not a viable therapeutic approach because of possible adverse side effects（专业术语，专业人员读到这里会觉得很有趣+_+）, including neurotoxicity. Instead, Mangalhara et al. propose modification of the electron transport chain in cancer cell mitochondria. （解决办法：对癌细胞线粒体中电子传递链进行修饰，下面是原理：）They found that the genetic ablation of methylation-controlled J protein (MCJ) – a CI-interacting protein – enhanced electron flow through CI. This reduced CII activity and led to succinate accumulation and higher antitumor immunity. This approach could improve immunotherapy success, especially in tumors with low expression of antigen processing and presentation genes.
The results of Mangalhara et al. inspire several follow-up questions. For instance, the observation that the inhibition of CII activity arrests tumor growth seemingly contradicts the established role of succinate as a tumor-promoting metabolite. This apparent discrepancy, also discussed by the authors, is likely explained by the context of where tumor-promoting CII mutations occur. Most loss-of-function CII mutations are inherited and thus are present from the early stages of tumorigenesis, promoting tumor initiation and progression. （以上为反方观点）Instead, Mangalhara et al. show that succinate has a proinflammatory effect on already-established tumors, affecting tumor growth and development. Furthermore, CII germline mutations might coexist with other oncogenic genetic alterations and stimulate tumor initiation and progression antitumor effect of succinate. （以上为正方观点）Future research should elucidate the molecular mechanisms by which succinate exerts an oncogenic or antitumor effect.（对于Mangalhara等人的发现，提出问题。阅读时，我们似乎可以看到辩论的双方，一方是Mangalhara等人，另一方是提出不同问题的一方，针锋相对的行文，读起来酣畅淋漓，虽然是说明文^_&）
It is not clear how succinate is exported from mitochondria to act in the nucleus and alter gene expression. Mitochondrial dicarboxylate carrier is the mitochondrial succinate carrier, but whether it is involved and whether alterations of its activity are implicated in the proposed succinate-histone demethylase – immunogenicity axis remain unexplored. Furthermore, succinate might diffuse into the nucleus through pores in the nuclear membrane. However, the mechanisms that maintain the two distinct pools of succinate – mitochondrial and nuclear – and prevent unnecessary interorganelle translocation remain elusive. As a possible explanation, recent studies have identified a noncanonical tricarboxylic acid cycle in the nucleus, which produces succinate locally. Nevertheless, it remains unclear how timely and precise transport of succinate from the mitochondria to the nucleus is achieved. Indeed, mitochondria, cytosol, and the nucleus differ in their biophysical properties, such as viscosity, which might be a barrier to interorganelle trafficking.（这一段主打一个：我不会，我不知道，我不理解&_&，说明文的常用技巧，文末提出未发现的问题，期待后来人解决）
The findings of Mangalhara et al. are exciting on multiple levels. The identification of a connection between mitochondrial metabolites and the epigenetic regulation of immunogenicity could have broad implications for immunology and for the study of conditions characterize by succinate accumulation, such as ischemia-reperfusion injury. （学科意义）These findings also suggest that targeting mitochondrial metabolism could be an effective approach for cancer immunotherapy, to boost the effects of immune checkpoint inhibitors.（实际意义）（Mangalhar等人发现的学科意义和实际意义）
metabolic control of antitumor immunity
Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation
The metabolism of cancer cells adapts to meet an increased need for the energy, biosynthesis, and antioxidants required for proliferation, tumor growth, and metastasis. Yet, whether this metabolic reprogramming affects the recognition and elimination of cancer cells by immune cells has not been well investigated. Mangalhara et al. report a connection between a cancer cell’s mitochondrial metabolism and its ability to evoke an immune response in a mouse model of melanoma. Specific perturbations of the mitochondrial electron transport chain increased succinate production in cancer cells. Succinate accumulation caused epigenetic rearrangements, which induced the expression of genes involved in antigen presentation. This promoted the detection of tumor cells by surveilling T cells – tumor immunogenicity. The identification of a mechanism by which mitochondrial metabolites shape tumor immunogenicity has potential for developing anticancer therapies.
The adaptive immune system comprises cells that recognize and response to various external stimuli through a process called antigen presentation. During the early stages of tumor development, cytotoxic immune cells, such as CD8+ T cells, recognize and eliminate immunogenic cancer cells, preventing tumor growth and metastasis. However, as they progress, tumors often acquire properties that allow them to escape immune detection. metabolism of immune cells is an important determinant of their function, including anticancer immunity. But whether metabolism in cancer cells affects their immunogenicity has been an open question. Mangalhara et al. assessed the role of complex I (CI) and complex II (CII) of the mitochondrial electron transport chain on melanoma growth. Pharmacological inhibition or genetic ablation of CII in mice enhanced the antitumor immune response by increasing antigen presentation by melanoma cells. This blocked tumor growth.
How is CII inhibition in cancer cells connected to the antitumor immune response? metabolism is tightly linked to epigenetics; various metabolites act as substrates or cofactors for DNA- and histone-modifying enzymes that regulate the chromatin landscape and thus, gene expression. For example, α-ketoglutarate, which is produced in mitochondria as part of the tricarboxylic acid cycle, is required for the activity of histone demethylases. The function of these enzymes is also regulated by competitive inhibitors, most of which are tricarboxylic acid cycle intermediates, such as succinate.
Mangalhara et al. demonstrate that in tumor cells succinate accumulation resulting from CII inhibition decreased the α-ketoglutarate/succinate ratio, which subsequently inhibited histone demethylases. The inhibition of these epigenetic enzymes increased the trimethylation of histone 3 lysine4 (H3K4) and H3K36 on genes involved in antigen processing and presentation, which induced the expression of these genes and activated T cell-mediated killing of tumor cells. These changes were reversed by the addition of α-ketoglutarate, which reactivates histone demethylases.
The systemic inhibition of CII activity is not a viable therapeutic approach because of possible adverse side effects, including neurotoxicity. Instead, Mangalhara et al. propose modification of the electron transport chain in cancer cell mitochondria. They found that the genetic ablation of methylation-controlled J protein (MCJ) – a CI-interacting protein – enhanced electron flow through CI. This reduced CII activity and led to succinate accumulation and higher antitumor immunity. This approach could improve immunotherapy success, especially in tumors with low expression of antigen processing and presentation genes.
The results of Mangalhara et al. inspire several follow-up questions. For instance, the observation that the inhibition of CII activity arrests tumor growth seemingly contradicts the established role of succinate as a tumor-promoting metabolite. This apparent discrepancy, also discussed by the authors, is likely explained by the context of where tumor-promoting CII mutations occur. Most loss-of-function CII mutations are inherited and thus are present from the early stages of tumorigenesis, promoting tumor initiation and progression. Instead, Mangalhara et al. show that succinate has a proinflammatory effect on already-established tumors, affecting tumor growth and development. Furthermore, CII germline mutations might coexist with other oncogenic genetic alterations and stimulate tumor initiation and progression antitumor effect of succinate. Future research should elucidate the molecular mechanisms by which succinate exerts an oncogenic or antitumor effect.
It is not clear how succinate is exported from mitochondria to act in the nucleus and alter gene expression. Mitochondrial dicarboxylate carrier is the mitochondrial succinate carrier, but whether it is involved and whether alterations of its activity are implicated in the proposed succinate-histone demethylase – immunogenicity axis remain unexplored. Furthermore, succinate might diffuse into the nucleus through pores in the nuclear membrane. However, the mechanisms that maintain the two distinct pools of succinate – mitochondrial and nuclear – and prevent unnecessary interorganelle translocation remain elusive. As a possible explanation, recent studies have identified a noncanonical tricarboxylic acid cycle in the nucleus, which produces succinate locally. Nevertheless, it remains unclear how timely and precise transport of succinate from the mitochondria to the nucleus is achieved. Indeed, mitochondria, cytosol, and the nucleus differ in their biophysical properties, such as viscosity, which might be a barrier to interorganelle trafficking.
The findings of Mangalhara et al. are exciting on multiple levels. The identification of a connection between mitochondrial metabolites and the epigenetic regulation of immunogenicity could have broad implications for immunology and for the study of conditions characterize by succinate accumulation, such as ischemia-reperfusion injury. These findings also suggest that targeting mitochondrial metabolism could be an effective approach for cancer immunotherapy, to boost the effects of immune checkpoint inhibitors.
