{"title":"癌症恶病质中的神经炎症导致冷漠。","authors":"Bingjun Ha, Xuetao Cao","doi":"10.1002/cac2.70055","DOIUrl":null,"url":null,"abstract":"<p>Neuro-immune modulation has attracted growing attention in recent years, particularly in elucidating neuro-immune interactions within the tumor microenvironment (TME). The nervous system actively monitors immune activity within the TME, transmits these signals to the brain for integrative processing, and acts back on the TME, forming a neuroimmune regulatory circuit to affect antitumor response and therapeutic outcomes [<span>1</span>]. Accumulating evidence demonstrates that the nervous system critically regulates tumor metastasis through the release of neurotransmitters and neurotrophic factors [<span>2</span>]. However, the precise mechanisms by which the nervous system contributes to the pathogenesis of cancer cachexia remain poorly understood. Cancer cachexia represents a multifactorial wasting syndrome characterized by progressive weight loss, muscle atrophy, and metabolic dysregulation, predominantly occurring in advanced-stage cancer patients [<span>3</span>]. Pro-inflammatory cytokines, particularly Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α; historically termed cachectin), have been extensively implicated in tumor progression [<span>4</span>]. These mediators promote cachexia through direct actions on muscle and adipose tissue [<span>3</span>]. Beyond their established roles in metabolic dysregulation and muscle wasting, these cytokines are increasingly recognized for their involvement in cytokine release syndrome associated with new-generation cancer immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapy [<span>5</span>]. Notably, IL-6 exhibits pleiotropic functions in neural regulation. Social stress exposure induces structural and functional alterations in the blood-brain barrier (BBB), enabling increased extravasation of circulating IL-6 into brain regions implicated in affective regulation, ultimately driving the manifestation of depressive symptoms [<span>6</span>]. Given its dual role in neuroinflammation and metabolic dysregulation, IL-6 may contribute to the pathogenesis of cachexia-associated neurological symptoms. Despite these advances, the neurobehavioral manifestations of cachexia, particularly depression-like behaviors, remain virtually unexplored. While systemic inflammation is known to impair diverse neurological functions, how cachexia induces these behaviors through central nervous system (CNS) mechanisms remains to be determined.</p><p>In a recent study, Zhu et al. [<span>7</span>] addressed this critical knowledge gap by demonstrating how IL-6 modulates cachexia-associated apathy. To investigate the impact of cachexia on motivation, they used a preclinical model of subcutaneous colon cancer-bearing mice. To account for individual differences in disease progression, they aligned the variable cachexia onset data to the endpoint and found that the most significant weight loss occurred during the last 3 days before death. In the motivation behavior assay, cachectic mice showed a marked reduction in operant actions and food intake. During the foraging decision task, cachectic mice exhibited both impaired accuracy in water-port recognition and diminished water intake, indicating heightened effort sensitivity. Notably, no signs of anhedonia (as measured by the sucrose preference test) or behavioral despair (tail suspension and forced swim tests) were observed. These findings define a unique motivational deficit profile characterized by apathy-like features that are distinct from classical depression-related phenotypes like anhedonia or despair.</p><p>To identify the cytokine-mediated mechanisms underlying motivational deficits in cancer cachexia, Zhu et al. [<span>7</span>] performed a systematic cytokine screening in both plasma and brain samples from cancer cachexia mouse models. Subsequent analyses revealed elevated IL-6 levels in both the peripheral blood and brain tissue of cachectic mice. Evans blue staining revealed increased BBB permeability, allowing peripheral IL-6 to infiltrate the brain parenchyma. Notably, peripheral administration of an IL-6-neutralizing antibody prolonged survival in cancer cachexia mouse models, indicating the critical role of IL-6 in driving cachexia progression.</p><p>Next, Zhu et al. [<span>7</span>] performed cellular-resolution mapping of neuronal activity by monitoring the expression of the immediate early gene <i>c-Fos</i>, a well-established marker of neuronal activation. Whole-brain neuronal activation mapping identified significant differences in 17 brain regions, with the lateral parabrachial nucleus (PBN) showing the most pronounced activation. The PBN serves as a neural hub for the multimodal integration of interoceptive and nociceptive signals. Its activation pattern is consistent with well-characterized neurocircuitry mechanisms governing appetite regulation and cancer-associated anorexia [<span>8</span>]. In addition, the medial shell of the nucleus accumbens (mNAc-sh) was also activated, while the ventral tegmental area (VTA) exhibited reduced activity. Behavioral assays further revealed impaired reward-induced dopamine release in the NAc of cachectic mice. Interventions such as IL-6 neutralization, optogenetic activation of the VTA-NAc circuit, or administration of NAc-targeted D2 receptor agonist restored dopamine release and ameliorated behavioral deficits. Electrophysiological results indicated altered VTA-NAc dopaminergic projections in cachexia, including decreased firing frequency and enhanced spontaneous inhibitory postsynaptic currents. These findings collectively indicate that replenishing dopamine levels can rescue motivation deficits induced by cachexia.</p><p>To further delineate the main source of inhibition of VTA dopaminergic neurons in cancer cachexia mouse models, Zhu et al. [<span>7</span>] next investigated the synaptic and circuit mechanisms responsible for the reduced VTA activation. Viral tracing implicated the PBN and substantia nigra pars reticulata (SNpr) as key upstream inhibitors of VTA dopaminergic neurons. In cancer cachexia mouse models, SNpr neurons showed heightened excitatory postsynaptic currents, while the PBN-VTA circuit exhibited strengthened inhibitory synaptic transmission. The area postrema (ArP), a circumventricular organ lacking a BBB, serves as a sensing hub for peripheral inflammatory signals. The observed interleukin-6 receptor (IL-6R) high expression in the ArP suggests potential cytokine sensitivity. Furthermore, its neurons project to the PBN [<span>9</span>]. These findings position the ArP as a critical neural substrate underlying cytokine-mediated motivational deficit in cachexia. Under healthy conditions, IL-6 is largely restricted by intact BBB tight junctions, which prevent it from entering the CNS. However, during inflammation, pro-inflammatory cytokines downregulate tight junction proteins, such as claudin-5 and ZO-1, increasing BBB permeability and facilitating IL-6 translocation. IL-6R knockdown (KD) in the ArP or ablation of ArP-to-PBN neurons rescued motivational deficits. Finally, they investigated whether the projection of ArP-to-PBN could modulate mesolimbic dopamine levels. Optical stimulation of the ArP-to-PBN projection mimicked the dopamine reduction observed in cachexia. In contrast, eliminating the projection of ArP-to-PBN alleviated the motivational deficits caused by cachexia.</p><p>In summary, the study by Zhu et al. [<span>7</span>] delineates a previously unrecognized IL-6-mediated neuro-immune axis, wherein tumor-derived IL-6 acts on the brain to suppress dopamine release, thereby inducing motivational deficits and exacerbating cancer cachexia-associated apathy (Figure 1). This pathway demonstrates that inflammation activates specific neural circuits rather than causing widespread neural damage or cumulative nerve injury. These findings not only establish a mechanistic link between systemic IL-6 and neurobehavioral decline in advanced cancer but also identify IL-6 blockade as a potential therapeutic strategy to restore motivation and improve patients’ quality of life.</p><p>Although the study has identified the key role of IL-6 in cachexia-associated apathy behavior, the molecular mechanisms within the ArP neurons and the potential involvement of other cytokines can be further studied. Future studies should employ single-cell transcriptomics and functional neuroimaging to elucidate cytokine-mediated dysfunction in ArP neurons during cachexia, while systematically exploring potential synergies between IL-6 and related mediators using humanized models to bridge mechanistic and translational insights. In cancer cachexia, IL-6 has previously been shown to mediate the neuropathological process of cachexia through the ArP. Circulating IL-6 activates ArP neurons, and knocking down IL-6 receptors in the ArP region significantly alleviates symptoms and prolongs survival [<span>10</span>]. That said, the ArP plays a crucial role in motivational behavior deficits caused by neuroinflammation. Clinically, IL-6 blockade has shown mixed results in cancer cachexia. Monoclonal antibodies blocking IL-6 signaling have demonstrated improvements in patient self-rated appetite and fatigue. However, the clinical application of IL-6 blockade in cancer cachexia must balance its neuroinflammatory benefits against systemic risks, including immunosuppression and potential effects on tumor progression. While BBB penetration poses challenges, cachexia-induced barrier disruption may facilitate CNS delivery. Alternative strategies such as trans-signaling blockade or targeted nanoparticles could optimize therapeutic specificity. Additional work is required to explore the IL-6 receptor signaling pathway in these neuronal populations and examine the potential roles of other cytokines in regulating brain behavior. Therefore, a better understanding of how the CNS responds to pro-inflammatory cytokine signals to modulate bodily functions and behavior will be critical for developing next-generation cancer therapies.</p><p>Bingjun Ha drafted the manuscript and generated the figure. Xuetao Cao supervised and revised the manuscript. All authors read and approved the final manuscript.</p><p>The authors declare that they have no competing interests.</p><p>Not applicable.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 10","pages":"1334-1337"},"PeriodicalIF":24.9000,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70055","citationCount":"0","resultStr":"{\"title\":\"Neuroinflammation drives apathy in cancer cachexia\",\"authors\":\"Bingjun Ha, Xuetao Cao\",\"doi\":\"10.1002/cac2.70055\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Neuro-immune modulation has attracted growing attention in recent years, particularly in elucidating neuro-immune interactions within the tumor microenvironment (TME). The nervous system actively monitors immune activity within the TME, transmits these signals to the brain for integrative processing, and acts back on the TME, forming a neuroimmune regulatory circuit to affect antitumor response and therapeutic outcomes [<span>1</span>]. Accumulating evidence demonstrates that the nervous system critically regulates tumor metastasis through the release of neurotransmitters and neurotrophic factors [<span>2</span>]. However, the precise mechanisms by which the nervous system contributes to the pathogenesis of cancer cachexia remain poorly understood. Cancer cachexia represents a multifactorial wasting syndrome characterized by progressive weight loss, muscle atrophy, and metabolic dysregulation, predominantly occurring in advanced-stage cancer patients [<span>3</span>]. Pro-inflammatory cytokines, particularly Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α; historically termed cachectin), have been extensively implicated in tumor progression [<span>4</span>]. These mediators promote cachexia through direct actions on muscle and adipose tissue [<span>3</span>]. Beyond their established roles in metabolic dysregulation and muscle wasting, these cytokines are increasingly recognized for their involvement in cytokine release syndrome associated with new-generation cancer immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapy [<span>5</span>]. Notably, IL-6 exhibits pleiotropic functions in neural regulation. Social stress exposure induces structural and functional alterations in the blood-brain barrier (BBB), enabling increased extravasation of circulating IL-6 into brain regions implicated in affective regulation, ultimately driving the manifestation of depressive symptoms [<span>6</span>]. Given its dual role in neuroinflammation and metabolic dysregulation, IL-6 may contribute to the pathogenesis of cachexia-associated neurological symptoms. Despite these advances, the neurobehavioral manifestations of cachexia, particularly depression-like behaviors, remain virtually unexplored. While systemic inflammation is known to impair diverse neurological functions, how cachexia induces these behaviors through central nervous system (CNS) mechanisms remains to be determined.</p><p>In a recent study, Zhu et al. [<span>7</span>] addressed this critical knowledge gap by demonstrating how IL-6 modulates cachexia-associated apathy. To investigate the impact of cachexia on motivation, they used a preclinical model of subcutaneous colon cancer-bearing mice. To account for individual differences in disease progression, they aligned the variable cachexia onset data to the endpoint and found that the most significant weight loss occurred during the last 3 days before death. In the motivation behavior assay, cachectic mice showed a marked reduction in operant actions and food intake. During the foraging decision task, cachectic mice exhibited both impaired accuracy in water-port recognition and diminished water intake, indicating heightened effort sensitivity. Notably, no signs of anhedonia (as measured by the sucrose preference test) or behavioral despair (tail suspension and forced swim tests) were observed. These findings define a unique motivational deficit profile characterized by apathy-like features that are distinct from classical depression-related phenotypes like anhedonia or despair.</p><p>To identify the cytokine-mediated mechanisms underlying motivational deficits in cancer cachexia, Zhu et al. [<span>7</span>] performed a systematic cytokine screening in both plasma and brain samples from cancer cachexia mouse models. Subsequent analyses revealed elevated IL-6 levels in both the peripheral blood and brain tissue of cachectic mice. Evans blue staining revealed increased BBB permeability, allowing peripheral IL-6 to infiltrate the brain parenchyma. Notably, peripheral administration of an IL-6-neutralizing antibody prolonged survival in cancer cachexia mouse models, indicating the critical role of IL-6 in driving cachexia progression.</p><p>Next, Zhu et al. [<span>7</span>] performed cellular-resolution mapping of neuronal activity by monitoring the expression of the immediate early gene <i>c-Fos</i>, a well-established marker of neuronal activation. Whole-brain neuronal activation mapping identified significant differences in 17 brain regions, with the lateral parabrachial nucleus (PBN) showing the most pronounced activation. The PBN serves as a neural hub for the multimodal integration of interoceptive and nociceptive signals. Its activation pattern is consistent with well-characterized neurocircuitry mechanisms governing appetite regulation and cancer-associated anorexia [<span>8</span>]. In addition, the medial shell of the nucleus accumbens (mNAc-sh) was also activated, while the ventral tegmental area (VTA) exhibited reduced activity. Behavioral assays further revealed impaired reward-induced dopamine release in the NAc of cachectic mice. Interventions such as IL-6 neutralization, optogenetic activation of the VTA-NAc circuit, or administration of NAc-targeted D2 receptor agonist restored dopamine release and ameliorated behavioral deficits. Electrophysiological results indicated altered VTA-NAc dopaminergic projections in cachexia, including decreased firing frequency and enhanced spontaneous inhibitory postsynaptic currents. These findings collectively indicate that replenishing dopamine levels can rescue motivation deficits induced by cachexia.</p><p>To further delineate the main source of inhibition of VTA dopaminergic neurons in cancer cachexia mouse models, Zhu et al. [<span>7</span>] next investigated the synaptic and circuit mechanisms responsible for the reduced VTA activation. Viral tracing implicated the PBN and substantia nigra pars reticulata (SNpr) as key upstream inhibitors of VTA dopaminergic neurons. In cancer cachexia mouse models, SNpr neurons showed heightened excitatory postsynaptic currents, while the PBN-VTA circuit exhibited strengthened inhibitory synaptic transmission. The area postrema (ArP), a circumventricular organ lacking a BBB, serves as a sensing hub for peripheral inflammatory signals. The observed interleukin-6 receptor (IL-6R) high expression in the ArP suggests potential cytokine sensitivity. Furthermore, its neurons project to the PBN [<span>9</span>]. These findings position the ArP as a critical neural substrate underlying cytokine-mediated motivational deficit in cachexia. Under healthy conditions, IL-6 is largely restricted by intact BBB tight junctions, which prevent it from entering the CNS. However, during inflammation, pro-inflammatory cytokines downregulate tight junction proteins, such as claudin-5 and ZO-1, increasing BBB permeability and facilitating IL-6 translocation. IL-6R knockdown (KD) in the ArP or ablation of ArP-to-PBN neurons rescued motivational deficits. Finally, they investigated whether the projection of ArP-to-PBN could modulate mesolimbic dopamine levels. Optical stimulation of the ArP-to-PBN projection mimicked the dopamine reduction observed in cachexia. In contrast, eliminating the projection of ArP-to-PBN alleviated the motivational deficits caused by cachexia.</p><p>In summary, the study by Zhu et al. [<span>7</span>] delineates a previously unrecognized IL-6-mediated neuro-immune axis, wherein tumor-derived IL-6 acts on the brain to suppress dopamine release, thereby inducing motivational deficits and exacerbating cancer cachexia-associated apathy (Figure 1). This pathway demonstrates that inflammation activates specific neural circuits rather than causing widespread neural damage or cumulative nerve injury. These findings not only establish a mechanistic link between systemic IL-6 and neurobehavioral decline in advanced cancer but also identify IL-6 blockade as a potential therapeutic strategy to restore motivation and improve patients’ quality of life.</p><p>Although the study has identified the key role of IL-6 in cachexia-associated apathy behavior, the molecular mechanisms within the ArP neurons and the potential involvement of other cytokines can be further studied. Future studies should employ single-cell transcriptomics and functional neuroimaging to elucidate cytokine-mediated dysfunction in ArP neurons during cachexia, while systematically exploring potential synergies between IL-6 and related mediators using humanized models to bridge mechanistic and translational insights. In cancer cachexia, IL-6 has previously been shown to mediate the neuropathological process of cachexia through the ArP. Circulating IL-6 activates ArP neurons, and knocking down IL-6 receptors in the ArP region significantly alleviates symptoms and prolongs survival [<span>10</span>]. That said, the ArP plays a crucial role in motivational behavior deficits caused by neuroinflammation. Clinically, IL-6 blockade has shown mixed results in cancer cachexia. Monoclonal antibodies blocking IL-6 signaling have demonstrated improvements in patient self-rated appetite and fatigue. However, the clinical application of IL-6 blockade in cancer cachexia must balance its neuroinflammatory benefits against systemic risks, including immunosuppression and potential effects on tumor progression. While BBB penetration poses challenges, cachexia-induced barrier disruption may facilitate CNS delivery. Alternative strategies such as trans-signaling blockade or targeted nanoparticles could optimize therapeutic specificity. Additional work is required to explore the IL-6 receptor signaling pathway in these neuronal populations and examine the potential roles of other cytokines in regulating brain behavior. Therefore, a better understanding of how the CNS responds to pro-inflammatory cytokine signals to modulate bodily functions and behavior will be critical for developing next-generation cancer therapies.</p><p>Bingjun Ha drafted the manuscript and generated the figure. Xuetao Cao supervised and revised the manuscript. All authors read and approved the final manuscript.</p><p>The authors declare that they have no competing interests.</p><p>Not applicable.</p>\",\"PeriodicalId\":9495,\"journal\":{\"name\":\"Cancer Communications\",\"volume\":\"45 10\",\"pages\":\"1334-1337\"},\"PeriodicalIF\":24.9000,\"publicationDate\":\"2025-08-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70055\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Communications\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cac2.70055\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Communications","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cac2.70055","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Neuroinflammation drives apathy in cancer cachexia
Neuro-immune modulation has attracted growing attention in recent years, particularly in elucidating neuro-immune interactions within the tumor microenvironment (TME). The nervous system actively monitors immune activity within the TME, transmits these signals to the brain for integrative processing, and acts back on the TME, forming a neuroimmune regulatory circuit to affect antitumor response and therapeutic outcomes [1]. Accumulating evidence demonstrates that the nervous system critically regulates tumor metastasis through the release of neurotransmitters and neurotrophic factors [2]. However, the precise mechanisms by which the nervous system contributes to the pathogenesis of cancer cachexia remain poorly understood. Cancer cachexia represents a multifactorial wasting syndrome characterized by progressive weight loss, muscle atrophy, and metabolic dysregulation, predominantly occurring in advanced-stage cancer patients [3]. Pro-inflammatory cytokines, particularly Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α; historically termed cachectin), have been extensively implicated in tumor progression [4]. These mediators promote cachexia through direct actions on muscle and adipose tissue [3]. Beyond their established roles in metabolic dysregulation and muscle wasting, these cytokines are increasingly recognized for their involvement in cytokine release syndrome associated with new-generation cancer immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapy [5]. Notably, IL-6 exhibits pleiotropic functions in neural regulation. Social stress exposure induces structural and functional alterations in the blood-brain barrier (BBB), enabling increased extravasation of circulating IL-6 into brain regions implicated in affective regulation, ultimately driving the manifestation of depressive symptoms [6]. Given its dual role in neuroinflammation and metabolic dysregulation, IL-6 may contribute to the pathogenesis of cachexia-associated neurological symptoms. Despite these advances, the neurobehavioral manifestations of cachexia, particularly depression-like behaviors, remain virtually unexplored. While systemic inflammation is known to impair diverse neurological functions, how cachexia induces these behaviors through central nervous system (CNS) mechanisms remains to be determined.
In a recent study, Zhu et al. [7] addressed this critical knowledge gap by demonstrating how IL-6 modulates cachexia-associated apathy. To investigate the impact of cachexia on motivation, they used a preclinical model of subcutaneous colon cancer-bearing mice. To account for individual differences in disease progression, they aligned the variable cachexia onset data to the endpoint and found that the most significant weight loss occurred during the last 3 days before death. In the motivation behavior assay, cachectic mice showed a marked reduction in operant actions and food intake. During the foraging decision task, cachectic mice exhibited both impaired accuracy in water-port recognition and diminished water intake, indicating heightened effort sensitivity. Notably, no signs of anhedonia (as measured by the sucrose preference test) or behavioral despair (tail suspension and forced swim tests) were observed. These findings define a unique motivational deficit profile characterized by apathy-like features that are distinct from classical depression-related phenotypes like anhedonia or despair.
To identify the cytokine-mediated mechanisms underlying motivational deficits in cancer cachexia, Zhu et al. [7] performed a systematic cytokine screening in both plasma and brain samples from cancer cachexia mouse models. Subsequent analyses revealed elevated IL-6 levels in both the peripheral blood and brain tissue of cachectic mice. Evans blue staining revealed increased BBB permeability, allowing peripheral IL-6 to infiltrate the brain parenchyma. Notably, peripheral administration of an IL-6-neutralizing antibody prolonged survival in cancer cachexia mouse models, indicating the critical role of IL-6 in driving cachexia progression.
Next, Zhu et al. [7] performed cellular-resolution mapping of neuronal activity by monitoring the expression of the immediate early gene c-Fos, a well-established marker of neuronal activation. Whole-brain neuronal activation mapping identified significant differences in 17 brain regions, with the lateral parabrachial nucleus (PBN) showing the most pronounced activation. The PBN serves as a neural hub for the multimodal integration of interoceptive and nociceptive signals. Its activation pattern is consistent with well-characterized neurocircuitry mechanisms governing appetite regulation and cancer-associated anorexia [8]. In addition, the medial shell of the nucleus accumbens (mNAc-sh) was also activated, while the ventral tegmental area (VTA) exhibited reduced activity. Behavioral assays further revealed impaired reward-induced dopamine release in the NAc of cachectic mice. Interventions such as IL-6 neutralization, optogenetic activation of the VTA-NAc circuit, or administration of NAc-targeted D2 receptor agonist restored dopamine release and ameliorated behavioral deficits. Electrophysiological results indicated altered VTA-NAc dopaminergic projections in cachexia, including decreased firing frequency and enhanced spontaneous inhibitory postsynaptic currents. These findings collectively indicate that replenishing dopamine levels can rescue motivation deficits induced by cachexia.
To further delineate the main source of inhibition of VTA dopaminergic neurons in cancer cachexia mouse models, Zhu et al. [7] next investigated the synaptic and circuit mechanisms responsible for the reduced VTA activation. Viral tracing implicated the PBN and substantia nigra pars reticulata (SNpr) as key upstream inhibitors of VTA dopaminergic neurons. In cancer cachexia mouse models, SNpr neurons showed heightened excitatory postsynaptic currents, while the PBN-VTA circuit exhibited strengthened inhibitory synaptic transmission. The area postrema (ArP), a circumventricular organ lacking a BBB, serves as a sensing hub for peripheral inflammatory signals. The observed interleukin-6 receptor (IL-6R) high expression in the ArP suggests potential cytokine sensitivity. Furthermore, its neurons project to the PBN [9]. These findings position the ArP as a critical neural substrate underlying cytokine-mediated motivational deficit in cachexia. Under healthy conditions, IL-6 is largely restricted by intact BBB tight junctions, which prevent it from entering the CNS. However, during inflammation, pro-inflammatory cytokines downregulate tight junction proteins, such as claudin-5 and ZO-1, increasing BBB permeability and facilitating IL-6 translocation. IL-6R knockdown (KD) in the ArP or ablation of ArP-to-PBN neurons rescued motivational deficits. Finally, they investigated whether the projection of ArP-to-PBN could modulate mesolimbic dopamine levels. Optical stimulation of the ArP-to-PBN projection mimicked the dopamine reduction observed in cachexia. In contrast, eliminating the projection of ArP-to-PBN alleviated the motivational deficits caused by cachexia.
In summary, the study by Zhu et al. [7] delineates a previously unrecognized IL-6-mediated neuro-immune axis, wherein tumor-derived IL-6 acts on the brain to suppress dopamine release, thereby inducing motivational deficits and exacerbating cancer cachexia-associated apathy (Figure 1). This pathway demonstrates that inflammation activates specific neural circuits rather than causing widespread neural damage or cumulative nerve injury. These findings not only establish a mechanistic link between systemic IL-6 and neurobehavioral decline in advanced cancer but also identify IL-6 blockade as a potential therapeutic strategy to restore motivation and improve patients’ quality of life.
Although the study has identified the key role of IL-6 in cachexia-associated apathy behavior, the molecular mechanisms within the ArP neurons and the potential involvement of other cytokines can be further studied. Future studies should employ single-cell transcriptomics and functional neuroimaging to elucidate cytokine-mediated dysfunction in ArP neurons during cachexia, while systematically exploring potential synergies between IL-6 and related mediators using humanized models to bridge mechanistic and translational insights. In cancer cachexia, IL-6 has previously been shown to mediate the neuropathological process of cachexia through the ArP. Circulating IL-6 activates ArP neurons, and knocking down IL-6 receptors in the ArP region significantly alleviates symptoms and prolongs survival [10]. That said, the ArP plays a crucial role in motivational behavior deficits caused by neuroinflammation. Clinically, IL-6 blockade has shown mixed results in cancer cachexia. Monoclonal antibodies blocking IL-6 signaling have demonstrated improvements in patient self-rated appetite and fatigue. However, the clinical application of IL-6 blockade in cancer cachexia must balance its neuroinflammatory benefits against systemic risks, including immunosuppression and potential effects on tumor progression. While BBB penetration poses challenges, cachexia-induced barrier disruption may facilitate CNS delivery. Alternative strategies such as trans-signaling blockade or targeted nanoparticles could optimize therapeutic specificity. Additional work is required to explore the IL-6 receptor signaling pathway in these neuronal populations and examine the potential roles of other cytokines in regulating brain behavior. Therefore, a better understanding of how the CNS responds to pro-inflammatory cytokine signals to modulate bodily functions and behavior will be critical for developing next-generation cancer therapies.
Bingjun Ha drafted the manuscript and generated the figure. Xuetao Cao supervised and revised the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
期刊介绍:
Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.