Pharmacological Reviews最新文献

{"title":"Metal-based antibody, nanobody, and peptide conjugates: Potential for breast cancer therapy.","authors":"Busra Kaya, Devina Laurencia, Maseeha Farha Ayoub, Mahan Gholam Azad, Mahendiran Dharmasivam, Des R Richardson","doi":"10.1016/j.pharmr.2025.100087","DOIUrl":"10.1016/j.pharmr.2025.100087","url":null,"abstract":"<p><p>Globally, breast cancer (BC) remains the leading cause of cancer death in women. BC profoundly impacts the physical and psychological well being of millions of families worldwide and significantly burdens the healthcare system and the economy. Although chemotherapy remains a key component in BC treatment, its effectiveness is often limited by severe side effects and the development of drug resistance, highlighting the urgent need for innovative therapeutic strategies. One strategy to minimize side effects involves conjugating anticancer agents with tumor-targeting molecules such as antibodies, nanobodies, or peptides to enhance their selective delivery to cancer cells. The success of platinum-based drugs such as cisplatin and carboplatin has urged the exploration of other metal-based complexes as therapeutic agents for BC. Metals, including copper, zinc, and gold, are considered promising candidates for anticancer therapy because of their well established cytotoxic properties and relatively low cost. This review examines the use of metal-based agents conjugated to tumor-targeting molecules for the treatment of BC. Additionally, we propose a novel approach to conjugate innovative thiosemicarbazone-copper complexes with a targeting moiety, aiming to overcome 2 major clinical challenges of current anticancer drugs: side effects and drug resistance. SIGNIFICANCE STATEMENT: Metal-based drugs possess potent anticancer properties through diverse mechanisms. However, current agents like cisplatin face 2 major challenges common to most anticancer therapies: toxic side effects and drug resistance. One strategy to address these issues is the conjugation of anticancer agents to specific tumor-targeting moieties, such as antibodies, nanobodies, or peptides. To further limit resistance development, drug conjugates can be designed to include a potent, multitargeted payload, such as a thiosemicarbazone-copper complex that targets lysosomes.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100087"},"PeriodicalIF":17.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102952","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":"Recent advances in the pharmacology of voltage-gated ion channels.","authors":"Diego Lopez-Mateos, Brandon John Harris, Adriana Hernández-González, Vladimir Yarov-Yarovoy, Heike Wulff","doi":"10.1016/j.pharmr.2025.100090","DOIUrl":"10.1016/j.pharmr.2025.100090","url":null,"abstract":"<p><p>Voltage-gated ion channels (VGICs) are critical regulators of membrane potential, cellular excitability, and calcium signaling in both excitable and nonexcitable tissues and constitute important drug targets for neurological, cardiovascular, and immunological diseases. This review describes recent progress in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels, highlighting clinical-stage compounds, emerging therapeutic modalities, and new strategies in VGIC drug discovery, emphasizing the increasingly central role of protein structures and artificial intelligence. Several compounds targeting VGICs have progressed to clinical trials for epilepsy, atrial fibrillation, psoriasis, and difficult-to-treat disorders, such as chronic pain, schizophrenia, major depression, and amyotrophic lateral sclerosis. The therapeutic landscape for VGIC-related disorders is expanding beyond traditional small molecules and antisense oligonucleotides and gene therapies targeting VGICs at the mRNA or gene level are currently in both early and late clinical trial stages for Dravet syndrome and developmental epileptic encephalopathy. The progression of such varied modalities suggests that the extensive efforts dedicated to elucidating VGIC biophysics and structure, coupled with rigorous target validation, are beginning to translate into therapeutic advancements. Furthermore, we discuss emerging discovery strategies, including the growing impact of VGIC structures, computational structural modeling, virtual screening of focused and ultralarge libraries, and artificial intelligence-driven redesign and de novo design of biologics. Although these approaches are poised to substantially accelerate the early stages of ion channel drug discovery, the clinical stages will continue to require careful selection of indications and thoughtful clinical trial design to fully realize the long-held potential of VGICs as drug targets. SIGNIFICANCE STATEMENT: Drug development for voltage-gated ion channels is widely considered to be challenging. This article reviews recent advances in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels by examining compounds currently in clinical trials, including emerging new therapeutic approaches such as antisense oligonucleotides and gene therapy. We then discuss noteworthy recent developments, including the increasing availability and impact of ion channel structures, structural modeling, virtual screening, and artificial intelligence-assisted protein design, which are likely to accelerate the early stages of ion channel drug discovery. Success of the later stages will continue to rely on rigorous target validation, and proper choices of clinical candidates and clinical trial design.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100090"},"PeriodicalIF":20.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing multiomics technologies and machine learning for advancing personalized theranostic approaches in atherosclerosis.","authors":"Soumaya Ben-Aicha, Prashant Srivastava, Georgios Kararigas, Yvan Devaux, Costanza Emanueli, Miron Sopic","doi":"10.1016/j.pharmr.2025.100091","DOIUrl":"10.1016/j.pharmr.2025.100091","url":null,"abstract":"<p><p>Evidence-based lipid-lowering therapies have significantly reduced, but not eradicated, atherosclerosis-induced cardiovascular disease, which remains a significant cause of morbidity and mortality around the world. This article focuses on precision medicine and examines the transformative potential of multiomics and machine learning in advancing theranostic approaches for atherosclerosis. The integration of multimodal data, known as multiomics, encompassing genomics and epigenomics, transcriptomics and epitranscriptomics, proteomics, metabolomics, and lipidomics, can support the comprehensive interrogation of molecular changes associated with disease initiation and progression. Machine learning algorithms are critical for identifying pertinent features of highly diverse and heterogeneous multiomic datasets. The combination of these new laboratory and data science technologies offers unprecedented opportunities for increasing precision in disease prediction, early detection, and monitoring, as well as more personalized treatments with current and new drugs. This article discusses the implications. It discusses their importance in the development and adoption of personalized medicine based on therapeutic approaches. SIGNIFICANCE STATEMENT: The review article explores new opportunities to develop and adopt theranostic strategies for atherosclerosis, derived from the integration of multiomics and machine learning to enhance personalized pharmacotherapy, precision prognostics, and diagnostics of atherosclerosis and atherosclerosis-derived cardiovascular diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100091"},"PeriodicalIF":17.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409717","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":"Erratum to \"Advances and challenges in experimental models of posttraumatic epilepsy for therapeutic interventions\" [Pharmacological Reviews 77 (2025) 100080].","authors":"Doodipala Samba Reddy,Victoria M Golub,Sreevidya Ramakrishnan,Severn B Churn,Lee A Shapiro,Jaclyn Iannucci,Asla Pitkänen,Aristea S Galanopoulou,Rama Maganti,Detlev Boison","doi":"10.1016/j.pharmr.2025.100099","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100099","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"2017 1","pages":"100099"},"PeriodicalIF":21.1,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403786","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":"Modern antidiabetic therapy by sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and dipeptidyl peptidase 4 inhibitors against cardiovascular diseases.","authors":"Sebastian Steven, Marin Kuntic, Thomas Münzel, Andreas Daiber","doi":"10.1016/j.pharmr.2025.100082","DOIUrl":"10.1016/j.pharmr.2025.100082","url":null,"abstract":"<p><p>Diabetes and related metabolic diseases have a high prevalence with increasing incidence and create a significant socioeconomic burden by their contribution to global mortality and disability-adjusted life years. According to data from the Global Burden of Disease Study, high fasting plasma glucose and high total cholesterol rank third and fourth in the list of global health risk factors, just behind high blood pressure and smoking. Diabetes adversely affects endothelial and cardiac function, thereby contributing significantly to the development and progression of cardiovascular diseases, which represents the leading health risk factors and causes of death worldwide. Oxidative stress and inflammation play a key role in the pathophysiology underlying diabetes mellitus and the associated cardiometabolic complications, such as metabolic dysfunction-associated fatty liver disease, hypertension, atherosclerosis, myocardial ischemia/reperfusion, and heart failure. Here, we highlight the beneficial effects of the modern antidiabetic drug classes of dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors on overall and cardiovascular mortality of diabetic individuals, with particular emphasis on their effects on oxidative stress, inflammation, and endothelial dysfunction. We discuss the mechanisms of action and pleiotropic beneficial effects and compare them with standard diabetic and cardiovascular therapy. SIGNIFICANCE STATEMENT: Modern antidiabetic drugs confer organ protection that goes beyond simple glucose-lowering. SGLT2 inhibitors and incretin-based drugs possess direct reno-, vasculo-, and cardioprotective effects that are based on potent antioxidant and anti-inflammatory properties. Other pleiotropic effects comprise improved lipid handling and weight loss, prevention of thrombosis and ischemic heart damage, and beneficial regulation of nitric oxide signaling and epigenetic and microbiotic pathways.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100082"},"PeriodicalIF":20.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144848239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell and tissue reprogramming: Unlocking a new era in medical drug discovery.","authors":"Chandan K Sen, Andrew J Friday, Sashwati Roy","doi":"10.1016/j.pharmr.2025.100077","DOIUrl":"10.1016/j.pharmr.2025.100077","url":null,"abstract":"<p><p>Recent advancements in cell and tissue biology have fundamentally changed our understanding of cellular behavior, revealing that both stem and nonstem cells exhibit remarkable plasticity and adaptability. This discovery has paved the way for revolutionary medical drug therapies that leverage cell and tissue reprogramming to repair or regenerate damaged tissues, offering new hope for conditions that were once considered irreversible. Tissue reprogramming involves the activation of specific molecular pathways to convert the function of residual tissue to compensate for the loss of tissue function to aging, trauma, or disease processes. By targeting these pathways, emerging drugs can promote regenerative processes, enabling the restoration of tissue function lost due to aging, injury, or disease. These therapies have shown promising results in preclinical studies addressing a wide range of diseases. Unlike traditional treatments, which focus primarily on managing symptoms, tissue reprogramming therapies offer a dynamic approach that can fundamentally alter cellular states, leading to functional recovery. This review explores the current state of cell and tissue reprogramming, highlighting its potential applications in regenerative medicine and the challenges that must be addressed for successful clinical translation. As our understanding of cellular plasticity continues to evolve, these innovative therapies stand at the forefront of a new era in medicine, with the potential to transform treatment paradigms and significantly improve patient outcomes across a wide range of conditions. SIGNIFICANCE STATEMENT: Breakthrough technologies have transformed our understanding of cell and tissue biology, uncovering that cells and tissues possess remarkable adaptability and fluidity in their roles. This revelation has opened up exciting possibilities in regenerative medicine, where emerging drug therapies aim to harness and reprogram cells to repair or regenerate damaged tissues. An emerging class of medical drugs will activate the body's natural regenerative abilities, offering the potential to restore tissue function lost due to aging, injury, or disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100077"},"PeriodicalIF":20.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of small molecule inhibitors of hypoxia-inducible factors for cancer therapy.","authors":"Gregg L Semenza","doi":"10.1016/j.pharmr.2025.100075","DOIUrl":"10.1016/j.pharmr.2025.100075","url":null,"abstract":"<p><p>The hypoxia-inducible factors (HIFs)-HIF-1 and HIF-2-play critical roles in cancer progression by controlling the transcription of thousands of genes across the full range of human cell types. Inhibition of their activity blocks cancer growth, vascularization, and metastasis in mouse models. Small-molecule HIF inhibitors, with varying degrees of specificity and mechanism of action have been reported to have antitumor activity in mouse models. An HIF-2 inhibitor, belzutifan, has recently been approved for the treatment of renal cell carcinoma. Dual HIF-1/2 inhibitors are being developed and are likely to have utility as cancer therapeutics, particularly in combination with immune checkpoint blockade. SIGNIFICANCE STATEMENT: Hypoxia-inducible factor inhibitors represent a powerful new therapeutic approach that has the potential to improve patient survival in many types of cancer when administered in combination with existing therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100075"},"PeriodicalIF":17.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760758","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":"Neuropeptides as transmitters and regulators of the locus coeruleus noradrenergic system.","authors":"Léa J Becker, Madison M Martin, Alex C Hughes, Bernard Mulvey, Chao-Cheng Kuo, Sean C Piantadosi, Michael R Bruchas, Keri Martinowich, Frank J Meye, Lindsay A Schwarz, David Weinshenker, Jordan G McCall, Danai Riga","doi":"10.1016/j.pharmr.2025.100081","DOIUrl":"10.1016/j.pharmr.2025.100081","url":null,"abstract":"<p><p>The locus coeruleus (LC), the brain's main source of noradrenaline, has received increased attention due to the recently unveiled heterogeneity of its cell types. Departing from the long-standing idea of molecular, anatomical, and functional uniformity of the structure, we now understand the LC as a multiplexed nucleus, capable of temporally precise and targeted neuromodulation of distinct brain regions and functions. The LC neuropeptidergic landscape provides a window into this remarkable neuronal diversity. Stemming from recent technological advances that have allowed for LC transcriptional profiling, a wealth of data on the (co)expression of LC neuropeptides and their cognate receptors has come to light. Peptidergic systems are ideally situated to exert neuromodulatory control over the LC noradrenergic system. This peptidergic control can occur both locally, within the LC and the neighboring peri-LC microcircuitry, and at distal LC terminal fields. The functional significance of LC neuropeptidergic signaling in physiological processes and pathological conditions is an emerging field. Here we compile existing literature on the expression, anatomical distribution, physiological effects, and, when available, behavioral role of the major neuropeptidergic populations of, and innervating, the LC and peri-LC. Furthermore, we highlight current methodologies that delineate LC peptidergic input/output, aiming at uncovering their functional role. Finally, we discuss how neuropeptidergic signaling enables LC modularity and thus sustains a multifaceted role of physiological noradrenaline release dynamics with a rich feature set of behavioral representations. SIGNIFICANCE STATEMENT: The locus coeruleus (LC) noradrenergic system influences a variety of neurophysiological processes to coordinate complex behaviors. These far-reaching neuromodulatory effects are not solely mediated by noradrenaline, but rather, by a variety of coreleased neuropeptides that can alter postsynaptic responses in LC terminal regions. In addition, the LC itself is regulated by a multitude of incoming peptidergic signals that drive wide-ranging changes in LC neuronal physiology and the subsequent patterns of noradrenaline release. It is important to understand how neuropeptide (co)transmitters and regulators of the LC can drive circuit-level plasticity and adaptive behavioral responses to changing environmental stimuli. This review compiles our current understanding of these processes, providing additionally crucial insights into the mechanisms underlying LC dysfunction and its many related neuropsychiatric conditions.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100081"},"PeriodicalIF":20.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cracking the EGFR code: Cancer biology, resistance mechanisms, and future therapeutic frontiers.","authors":"Yafei Du, Feride Karatekin, Wendy Kehan Wang, Wanjin Hong, Gandhi T K Boopathy","doi":"10.1016/j.pharmr.2025.100076","DOIUrl":"10.1016/j.pharmr.2025.100076","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) plays a crucial role in tumorigenesis across multiple cancer types. EGFR mutations, overexpression, amplifications, dysregulated signaling, and impaired receptor downregulation drive cancer progression, particularly in non-small cell lung cancer, glioblastoma, colorectal cancer, gastric cancer, and head and neck cancers. Over the past decades, EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved patient outcomes. However, drug resistance inevitably arises through on-target mutations, activation of bypass signaling pathways, and disruptions in receptor trafficking and degradation. To overcome resistance, novel therapeutic strategies such as new generation of tyrosine kinase inhibitors, antibody-drug conjugates, and targeted protein degradation approaches like proteolysis-targeting chimeras are being actively explored. Additionally, combination therapies targeting parallel or compensatory pathways are being explored in mitigating drug resistance. Advances in genomic profiling and liquid biopsy technologies further enable personalized treatment strategies tailored to individual genetic backgrounds. In this review, we provide an overview of EGFR signaling and examine the landscape of EGFR mutations and currently available targeted therapies, while highlighting key resistance mechanisms. Furthermore, emerging strategies designed to overcome resistance are discussed, offering insights into future directions for EGFR-targeted cancer treatment. SIGNIFICANCE STATEMENT: Epidermal growth factor receptor (EGFR) is a key driver of tumorigenesis across multiple cancers, with overexpression, mutations, and amplifications promoting disease progression and therapeutic resistance. Despite the success of EGFR-targeted therapies, resistance remains a significant barrier to sustainable efficacy. This review provides an overview of EGFR biology and therapy, resistance mechanisms, and emerging new therapeutic strategies. A deeper understanding of these aspects is crucial for overcoming resistance and guiding the development of more effective and personalized cancer treatments.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100076"},"PeriodicalIF":17.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659795","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":"Microbial-induced trained immunity for cancer immunotherapy.","authors":"Patricia Vuscan, Brenda Kischkel, Leo A B Joosten, Mihai G Netea","doi":"10.1016/j.pharmr.2025.100074","DOIUrl":"10.1016/j.pharmr.2025.100074","url":null,"abstract":"<p><p>Myeloid innate immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells, and dendritic cells, represent major components of the tumor microenvironment (TME), exhibiting remarkable plasticity and dual roles in cancer progression and immune regulation. In recent years, microbial-induced innate immune memory, also termed \"trained immunity\" (TRIM), has emerged as a novel strategy to reprogram myeloid cells into an immunostimulatory, antitumor state. In this review, we explore the intricate landscape of myeloid cells in cancer and examine how microbial ligands, such as the Bacillus Calmette-Guérin vaccine and β-glucan, reprogram both bone marrow progenitors and tissue-resident myeloid cells to enhance inflammatory and antitumor responses. Notable findings include the hematopoietic stem and progenitor cell reprogramming by Bacillus Calmette-Guérin for sustained anticancer immunity, and the enhanced granulopoiesis and neutrophil-mediated tumor killing mediated by β-glucan-induced TRIM. These mechanisms synergize with immunotherapies, such as immune checkpoint inhibitors, by reshaping the immunosuppressive TME and enhancing adaptive immunity. However, challenges remain, including the structural complexity of microbial products, the lack of predictive biomarkers, and the need for optimized dosing and delivery strategies. Addressing these gaps by introducing precise characterization of microbial-derived ligands, biomarker-driven patient selection through large-scale clinical trials, as well as the development of novel approaches for targeted therapy will be essential to harness the full potential of microbial-induced TRIM, ultimately paving the way for more effective and durable cancer immunotherapies. SIGNIFICANCE STATEMENT: Tumor-promoting myeloid cells within the tumor microenvironment remain a major barrier to effective cancer immunotherapy. Microbial-induced trained immunity offers a novel strategy to reprogram myeloid cells into an antitumor state. This review provides a comprehensive overview of myeloid cell populations in cancer and the mechanisms underlying microbial-induced trained immunity. It also highlights preclinical and clinical evidence demonstrating the efficacy of microbial-based strategies in overcoming immunosuppression and synergizing with existing immunotherapies, offering a promising approach to improve cancer treatment outcomes.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100074"},"PeriodicalIF":17.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567721","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}