Lucas Blanchard, Estefania Vina, Jerko Ljubetic, Cécile Meneur, Dorian Tarroux, Maria Baez, Alessandra Marino, Nathalie Ortega, David A Knorr, Jeffrey V Ravetch, Jean-Philippe Girard
{"title":"Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade.","authors":"Lucas Blanchard, Estefania Vina, Jerko Ljubetic, Cécile Meneur, Dorian Tarroux, Maria Baez, Alessandra Marino, Nathalie Ortega, David A Knorr, Jeffrey V Ravetch, Jean-Philippe Girard","doi":"10.1016/j.xcrm.2025.102141","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102141","url":null,"abstract":"<p><p>The lack of T cells in tumors is a major hurdle to successful immune checkpoint therapy (ICT). Therefore, therapeutic strategies promoting T cell recruitment into tumors are warranted to improve the treatment efficacy. Here, we report that Fc-optimized anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are potent remodelers of tumor vasculature that increase tumor-associated high endothelial venules (TA-HEVs), specialized blood vessels supporting lymphocyte entry into tumors. Mechanistically, this effect is dependent on the Fc domain of anti-CTLA-4 antibodies and CD4<sup>+</sup> T cells and involves interferon gamma (IFNγ). Unexpectedly, we find that the human anti-CTLA-4 antibody ipilimumab fails to increase TA-HEVs in a humanized mouse model. However, increasing its Fc effector function rescues the modulation of TA-HEVs, promotes CD4<sup>+</sup> and CD8<sup>+</sup> T cell infiltration into tumors, and sensitizes recalcitrant tumors to programmed cell death protein 1 (PD-1) blockade. Our findings suggest that Fc-optimized anti-CTLA-4 antibodies could be used to reprogram tumor vasculature in poorly immunogenic cold tumors and improve the efficacy of ICT.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102141"},"PeriodicalIF":11.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ruben Rodriguez, Anne Hergarden, Shyam Krishnan, Marikris Morales, Davina Lam, Ted Tracy, Teresa Tang, Avalon Patton, Craig Lee, Asmita Pant, Daniel A Erlanson, Johan Enquist, Derek Bone, Ray Fucini, Damian Bialonczyk, Stig K Hansen, Jian Luo, Manu V Chakravarthy
{"title":"Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy.","authors":"Ruben Rodriguez, Anne Hergarden, Shyam Krishnan, Marikris Morales, Davina Lam, Ted Tracy, Teresa Tang, Avalon Patton, Craig Lee, Asmita Pant, Daniel A Erlanson, Johan Enquist, Derek Bone, Ray Fucini, Damian Bialonczyk, Stig K Hansen, Jian Luo, Manu V Chakravarthy","doi":"10.1016/j.xcrm.2025.102156","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102156","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have recently been shown to play a significant role in the treatment of diabetes and obesity. Better understanding of their signaling and mechanism of action could further improve their therapeutic effects. In the current study, we investigate the impact of biased cyclic AMP (cAMP) signaling of GLP-1R and GIPR, individually, as well as the combined effects of a unimolecular dually biased GLP-1R/GIPR agonist, CT-859, on glucose, food consumption, and body weight regulation. Our data demonstrate that biased agonism of either GLP-1R or GIPR leads to better glycemic regulation, greater food intake suppression, and weight loss. In addition, concerted biased activation of both GLP-1R and GIPR results in substantially higher efficacy. Activation of GLP-1R and GIPR with a combination of individually biased agonists or via a dually biased unimolecular approach with CT-859 may provide significant therapeutic advantages for the treatment of diabetes and obesity.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102156"},"PeriodicalIF":11.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jack A Collora, Savannah F Steinhauser, Timothy C Davenport, Daniel C Lin, Amare Eshetu, Samana Zeidi, Rachel Kim, Cynthia Frank, Yuval Kluger, Sandra A Springer, Ya-Chi Ho
{"title":"Medications for opioid use disorder shape immune responses during chronic HIV infection.","authors":"Jack A Collora, Savannah F Steinhauser, Timothy C Davenport, Daniel C Lin, Amare Eshetu, Samana Zeidi, Rachel Kim, Cynthia Frank, Yuval Kluger, Sandra A Springer, Ya-Chi Ho","doi":"10.1016/j.xcrm.2025.102159","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102159","url":null,"abstract":"<p><p>People living with HIV (PLWHs) have higher risk of opioid use disorder (OUD). Whether medications for opioid use disorder (MOUDs) change immune responses in HIV infection is unknown. We examined the immune profiles in PLWHs before and 3 months after initiation of the μ opioid receptor agonist methadone, partial agonist buprenorphine, and antagonist naltrexone. Using single-cell DOGMA-seq, we profiled 29,462 peripheral blood immune cells in 12 PLWHs. We found that naltrexone treatment increased type I interferon (IFN) responses while buprenorphine increased tumor necrosis factor (TNF) responses in cytotoxic T cell population. We found that HIV+ cells in PLWHs with OUD upregulated PTPN13 and TAF5L, both of which are associated with HIV replication. We found trends suggesting increased HIV RNA expression after methadone and decreased HIV RNA expression after buprenorphine and naltrexone initiation. Overall, PLWHs treated with MOUD had improved immune responses and decreased HIV expression.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102159"},"PeriodicalIF":11.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nabil Smichi, Biswajit Khatua, Sergiy Kostenko, Cristiane de Oliveira, Bara El Kurdi, Kalpit Himmatbhai Devani, Shubham Trivedi, Megan Summers, Bryce McFayden, Sarah Navina, Krutika Patel, Sarah Jahangir, Marek Belohlavek, Vijay P Singh
{"title":"Visceral fat lipolysis by pancreatic lipases worsens heart failure.","authors":"Nabil Smichi, Biswajit Khatua, Sergiy Kostenko, Cristiane de Oliveira, Bara El Kurdi, Kalpit Himmatbhai Devani, Shubham Trivedi, Megan Summers, Bryce McFayden, Sarah Navina, Krutika Patel, Sarah Jahangir, Marek Belohlavek, Vijay P Singh","doi":"10.1016/j.xcrm.2025.102147","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102147","url":null,"abstract":"<p><p>Heart failure can be worse when associated with obesity, elevated serum pancreatic enzymes, elevated non-esterified fatty acids (NEFAs), or acute pancreatitis (AP). To understand this, here we study doxorubicin-induced heart failure, experimental AP, or pancreatic lipase-induced visceral fat necrosis in lean, genetically obese (ob/ob), or dual ob/ob pancreatic triglyceride lipase (PNLIP)-knockout mice. NEFA generation and resulting cardiac injury are measured. We note that ob/ob mice develop fat necrosis containing PNLIP and phospholipase A<sub>2</sub>. This generates excess NEFAs that worsen cardiac injury, cause hypotension, and reduce survival. All these are prevented by PNLIP deletion or pharmacologic inhibition. Live imaging shows that phospholipase A<sub>2</sub> damages adipocyte membranes, resulting in PNLIP entry and leakage of adipocyte lipases. PNLIP hydrolyzes adipose triglyceride, generates NEFAs, and causes lipid droplet loss and adipocyte necrosis. Therefore, pancreatic injury can worsen antecedent heart failure by leaked PNLIP, causing excessive visceral adipose lipolysis. Inhibition of such lipolysis may improve heart failure outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102147"},"PeriodicalIF":11.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cross-organ hierarchy of HLA molecular mismatches in donor-specific antibody development in solid organ transplantations.","authors":"Masaaki Hirata, Kazuto Tsukita, Takero Shindo, Shintaro Yagi, Takashi Ito, Satona Tanaka, Ryo Fujimoto, Hidenao Kayawake, Kenji Nakamura, Nobuhiro Fujiyama, Mitsuru Saito, Kimiko Yurugi, Rie Hishida, Arisa Kato, Atsushi Kawaguchi, Tomonori Habuchi, Takashi Kobayashi, Hiroshi Date, Etsuro Hatano","doi":"10.1016/j.xcrm.2025.102153","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102153","url":null,"abstract":"<p><p>Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) play a crucial role in antibody-mediated rejection, a major barrier to successful organ transplantation. Donor-recipient HLA molecular incompatibility critically influences DSA susceptibility, commonly assessed by analyzing mismatches in the HLA eplet repertoire. This study, including six distinct liver, lung, and kidney transplant cohorts from two centers (978 donor-recipient pairs), explores associations between individual eplet mismatches and DSA development. Certain mismatched eplets are strongly linked to DSA development, while others show weaker associations, a trend consistent across different organ types. Machine learning leverages these hierarchical associations to develop an eplet risk score (ERS), outperforming traditional eplet mismatch assessments. Furthermore, T cell proliferation in mixed lymphocyte reaction in vitro correlates with the ERS, attenuated by antibody-mediated inhibition of a mismatched DSA-associated eplet. These results establish the differential immunological impacts of mismatched HLA eplets as integral in clinical practice and therapeutic innovation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102153"},"PeriodicalIF":11.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin Bone, Nicola Cotugno, Chiara Pighi, Arianna Rotili, Seohyun Hong, Leah Carrere, Elena Morrocchi, Giuseppe Rubens Pascucci, Ce Gao, Nicole Colantoni, Weiwei Sun, Giovanna Leone, David R Collins, Mpho J Olatotse, Giovanna Del Principe, Toong Seng Tan, Melanie Lancien, Alessia Neri, Libera Sessa, Giulio Olivieri, Kailey Shapiro, Isabelle Roseto, Catherine Koofhethile, Elena Emili, Stefania Bernardi, Ann Chahroudi, Paolo Rossi, Bruce D Walker, Xu G Yu, Mathias Lichterfeld, Paolo Palma
{"title":"Distinct viral reservoirs and immune signatures in individuals on long-term antiretroviral therapy with perinatally acquired HIV-1.","authors":"Benjamin Bone, Nicola Cotugno, Chiara Pighi, Arianna Rotili, Seohyun Hong, Leah Carrere, Elena Morrocchi, Giuseppe Rubens Pascucci, Ce Gao, Nicole Colantoni, Weiwei Sun, Giovanna Leone, David R Collins, Mpho J Olatotse, Giovanna Del Principe, Toong Seng Tan, Melanie Lancien, Alessia Neri, Libera Sessa, Giulio Olivieri, Kailey Shapiro, Isabelle Roseto, Catherine Koofhethile, Elena Emili, Stefania Bernardi, Ann Chahroudi, Paolo Rossi, Bruce D Walker, Xu G Yu, Mathias Lichterfeld, Paolo Palma","doi":"10.1016/j.xcrm.2025.102150","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102150","url":null,"abstract":"<p><p>Early initiation of antiretroviral therapy (ART) following HIV-1 infection restricts the size of the latent reservoir, following both horizontal and vertical infections. Here, we comprehensively profile the reservoirs and immunological milieus of nine young adults who acquired HIV-1 perinatally and remained on suppressive long-term ART (median: 20 years) since infancy (LeukoHIV cohort). Genome-intact reservoirs are markedly smaller compared to a cohort of adults on suppressive ART started in adulthood, with some LeukoHIV individuals characterized by an absence or near absence of intact proviruses in up to a billion peripheral blood mononuclear cells (PBMCs). Higher frequencies of functional CD56<sup>bright</sup> natural killer (NK) cells with increased cytotoxic activity are detectable in the LeukoHIV cohort compared to an adult reference cohort, while one LeukoHIV participant displayed a potent HIV-1-specific CD8<sup>+</sup> T cell response. Collectively, our data suggest that long-term ART initiated in early life following perinatal transmission may facilitate an immune environment better equipped to restrict the HIV-1 reservoir.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102150"},"PeriodicalIF":11.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Combined therapy with DR5-targeting antibody-drug conjugate and CDK inhibitors as a strategy for advanced colorectal cancer.","authors":"Dongdong Zhou, Er'jiang Tang, Wenjun Wang, Youban Xiao, Jianming Huang, Jie Liu, Chao Zheng, Kai Zhang, Ruxia Hu, Feiqi Wang, Peng Xiong, Xin Chu, Weisong Li, Dongqin Liu, Xiangfu Zeng, Dexian Zheng, Liefeng Wang, Yong Zheng, Shuyong Zhang","doi":"10.1016/j.xcrm.2025.102158","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102158","url":null,"abstract":"<p><p>Targeted therapies for advanced microsatellite stable (MSS) subtype colorectal cancer (MSS-CRC) remain a clinical challenge. Here, we show that death receptor 5 (DR5) is elevated in both MSS and microsatellite instability-high (MSI-H) colorectal cancer (CRC) cohorts, highlighting its potential as a clinical target. Oba01, a clinical-stage DR5-targeting antibody-drug conjugate (ADC) delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE), shows superior efficacy in CRC cell lines, patient-derived xenografts and their corresponding organoids, irrespective of MSS or MSI-H status. Importantly, our functional multi-omics analysis reveals that the cell cycle pathway and cyclin-dependent kinases (CDKs) are key synergistic targets of Oba01's tumor-killing activity. We further show that Oba01 synergizes with the Food and Drug Administration (FDA)-approved CDK inhibitor abemaciclib in clinically relevant in vivo models. This synergy is also observed with other CDK inhibitors, underscoring the potential of combining Oba01 with CDK inhibition as a therapeutic strategy for advanced CRC, particularly the refractory MSS subtype.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102158"},"PeriodicalIF":11.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Junfen Xu, Qinghua Ji, Quanming Kong, Lijuan Lv, Bo Zhu, Xiufeng Huang, Zhengyun Chen, Ping Xu, Xiao Li, Weiwei Yin, Hui Wang
{"title":"Minimally invasive diagnosis of precancerous cervical lesions using single-cell peripheral immune atlas.","authors":"Junfen Xu, Qinghua Ji, Quanming Kong, Lijuan Lv, Bo Zhu, Xiufeng Huang, Zhengyun Chen, Ping Xu, Xiao Li, Weiwei Yin, Hui Wang","doi":"10.1016/j.xcrm.2025.102149","DOIUrl":"10.1016/j.xcrm.2025.102149","url":null,"abstract":"<p><p>Cervical cancer remains a major global health concern for women. Current screening methods are either invasive or lead to low participation and over-referral for colposcopy, particularly among high-risk human papillomavirus (HPV)-positive women. This study analyzes 613 participants with varying cervical lesions using mass cytometry by time-of-flight (CyTOF) to identify disease-specific peripheral immune signatures. A diagnostic model based on 23 immune features achieves ∼91% sensitivity and specificity for detecting precancerous and cancerous lesions. A separate model for HPV-positive women shows even higher accuracy (∼93% sensitivity, ∼95% specificity), especially in HPV16/18-positive cases (99% sensitivity, 100% specificity). In an independent validation cohort (n = 105), the model distinguishes cervical intraepithelial neoplasia (CIN) 2+ from ≤CIN1 with 86.5% sensitivity and 85.3% specificity (area under the curve [AUC] = 0.89). These findings support peripheral immune profiling as a minimally invasive and accurate biomarker strategy for early cervical cancer screening, particularly in HPV16/18-positive women.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102149"},"PeriodicalIF":11.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ultrabright ratiometric Raman-guided epilepsy surgery by intraoperatively visualizing proinflammatory microglia.","authors":"Cong Wang, Zhi Li, Xiao Zhu, Wanbing Sun, Yue Ding, Wenjia Duan, Difei Wang, Yiqing Jiang, Ming Chen, Yuncan Chen, Jiayi Hu, Zheping Cai, Jing Zhao, Junfeng Wang, Zhen Fan, Faming Zheng, Xingyu Zhou, Fang Xie, Jianping Zhang, Yihui Guan, Kui Yan, Zuhai Lei, Qinyue Wang, Luting Wang, Xiao Xiao, Hairong Zheng, Liang Chen, Cong Li, Ying Mao","doi":"10.1016/j.xcrm.2025.102155","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102155","url":null,"abstract":"<p><p>Resective surgery is an effective approach for long-term seizure control in drug-resistant focal epilepsy when the epileptic focus (EF) can be accurately delineated and removed. However, intraoperative mapping of EF with electrocorticography is laborious, time-consuming, and highly vulnerable to the effects of anesthesia. Here, we demonstrated that activated microglia can be reliable biomarkers for EF localization. Leveraging a newly developed ratiometric Raman nanosensor, ultraHOCls, we successfully visualize proinflammatory microglia in live epileptic mice, allowing for precise EF delineation without the interference of anesthesia. Compared to electrocorticography-guided surgery, ultraHOCl-guided surgery results in a substantial 61% reduction in total seizure burden in epileptic mouse models. Notably, ultraHOCls sprayed on freshly excised human brain tissues can effectively discriminate epileptic regions from non-epileptic tissues with high sensitivity (94.89%) and specificity (93.3%). This work provides an alternative strategy for delineating the EF intraoperatively, potentially revolutionizing surgery outcomes in epilepsy patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102155"},"PeriodicalIF":11.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hao Zhu, Xiaoyu Tong, Nancy B Carlisle, Hua Xie, Corey J Keller, Desmond J Oathes, Feng Liu, Charles B Nemeroff, Gregory A Fonzo, Yu Zhang
{"title":"Contrastive functional connectivity defines neurophysiology-informed symptom dimensions in major depression.","authors":"Hao Zhu, Xiaoyu Tong, Nancy B Carlisle, Hua Xie, Corey J Keller, Desmond J Oathes, Feng Liu, Charles B Nemeroff, Gregory A Fonzo, Yu Zhang","doi":"10.1016/j.xcrm.2025.102151","DOIUrl":"10.1016/j.xcrm.2025.102151","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is highly heterogeneous, posing challenges for effective treatment due to complex interactions between clinical symptoms and neurobiological features. To address this, we apply contrastive principal-component analysis to fMRI-based resting-state functional connectivity, isolating disorder-specific variations by contrasting data from 233 MDD patients and 285 healthy controls. Subsequently, we use sparse canonical correlation analysis to identify two significant dimensions linking distinct brain circuits with clinical profiles. One dimension relates to an internalizing-externalizing symptom spectrum involving visual and limbic networks and is associated with cognitive task reaction times. The other dimension, linked to personality traits protective against depression (e.g., extraversion), is driven by dorsal attention network connections and correlates with cognitive control and psychomotor performance. This approach illuminates stable symptom dimensions and their neurophysiological underpinnings, aiding in precision phenotyping for MDD and supporting the development of targeted, individualized therapeutic strategies for mental health care.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102151"},"PeriodicalIF":11.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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