Medical Oncology最新文献

{"title":"Immunogenic cell death: synergizing ferroptosis and cuproptosis to overcome immunotherapy resistance.","authors":"Mamdouh A Ragab, Mahmoud A Seliem","doi":"10.1007/s12032-026-03429-w","DOIUrl":"10.1007/s12032-026-03429-w","url":null,"abstract":"<p><p>The advent of immune checkpoint inhibitors has fundamentally changed the face of oncology, but the prevalence of primary and acquired resistance has led to the need for the development of novel approaches to remodel the immunosuppressive tumor microenvironment. Central to this challenge is the dichotomy between hot inflamed and cold (immune-excluded) tumors, which is increasingly associated with the immunogenicity of cell death modalities used by therapeutic agents. While apoptosis is largely immunologically silent, regulated cell death pathways driven by the catastrophic failure of mitochondrial metal ion homeostasis, i.e. ferroptosis, and the recently characterized cuproptosis, have emerged as potent drivers of immunogenic cell death. This review represents a comprehensive synthesis of the molecular mechanisms that control these metal-dependent lethal cascades, which includes a detailed account of the biochemical divergence of the iron-dependent Fenton chemistry versus the copper-dependent protein lipoylation and aggregation. We elucidate the role of the mitochondrion as a critical upstream contributor and signal amplifier where bioenergetics, iron-sulfur (Fe-S) cluster stability, and metal toxicity converge to trigger the release of damage-associated molecular patterns such as HMGB1 and ATP. Furthermore, we incorporate the emerging layer of epitranscriptomic regulation, showing how N6-methyladenosine (m6A) modifications influence the spatial architecture of the tumor, the expression of metal transporters and vulnerability genes (e.g. FDX1, SLC7A11) and determine the immune phenotype. By examining the synergistic potential of co-targeting ferroptosis and cuproptosis, we propose a therapeutic framework for overcoming immunotherapy resistance, which may potentially convert the metabolic vulnerabilities of cancer cells into immunological activating signals, hypothesized to drive durable anti-tumor immunity.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblasts in therapeutic resistance of hepatocellular carcinoma: evidence, mechanisms, and translational implications.","authors":"Tao Huang, Qiaoying Li, Zhaolan Yu, Zhigui Wu, Hanyao Cheng, Xinge Zhang, Liu Yang, Shurong Wang","doi":"10.1007/s12032-026-03435-y","DOIUrl":"10.1007/s12032-026-03435-y","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains difficult to treat because responses to tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are limited and heterogeneous. Cancer-associated fibroblasts (CAFs) can influence therapeutic responses through paracrine signaling, immune regulation, and extracellular matrix remodeling, but CAF-driven tumor progression should not be equated with therapeutic resistance. This review critically evaluates HCC-specific evidence according to defined drug exposure, treatment-related outcomes, and functional rescue. The most mechanistically resolved direct resistance mechanisms involve CAF-derived SPP1, which activates integrin-PKCα-dependent bypass signaling during sorafenib or lenvatinib treatment; CAF-derived CXCL12, which reduces sorafenib-induced apoptosis through CXCR4-dependent FOLR1 upregulation; and CAF-derived fibronectin extra domain A, which activates NF-κB-SHMT1-dependent redox adaptation during sorafenib exposure, with TLR4 proposed as the upstream receptor. These pathways are supported by genetic or pharmacological interventions that restore TKI sensitivity. By contrast, POSTN⁺ CAFs are associated with IL-6/IL-6R/STAT3-dependent macrophage recruitment, increased macrophage SPP1 expression, immune exclusion, and reduced ICI responsiveness, although selective reversal of this CAF program remains unproven. Progression-associated and cross-cancer findings are therefore considered separately from established resistance mechanisms.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor efficacy and safety profile of gallic acid in the murine sarcoma 180 model.","authors":"Greice Itamaro Heiden, Matheus Antoni da Silva Costa, Caroline Alfaia Silva, Felipe Mendes de Andrade de Carvalho, Ricardo Guimarães Amaral, Elena Riet Correa Rivero, Filipe Modolo, Rogério Gondak, Ricardo Luiz Cavalcanti de Albuquerque-Júnior","doi":"10.1007/s12032-026-03455-8","DOIUrl":"10.1007/s12032-026-03455-8","url":null,"abstract":"<p><p>Gallic acid (GA) is a plant-derived polyphenol with recognized anticancer activity, but in vivo evidence, especially in mesenchymal solid tumors, remains limited. This study investigated the antitumor effects and mechanistic pathways of GA in the murine Sarcoma 180 (S-180) model. Fifty male Swiss mice bearing S-180 tumors received oral GA (10, 25, or 50 mg/kg/day), 5-fluorouracil (5-FU; 25 mg/kg, intraperitoneal), or vehicle for seven days. Tumor weight and growth inhibition were assessed, along with histopathology and immunohistochemistry for proliferation (Ki-67, a proliferation marker), apoptosis (cleaved caspase-3 and caspase-8, Bcl-2-associated X protein [Bax], and B-cell lymphoma 2 [Bcl-2]), nuclear factor kappa B (NF-κB), and systemic toxicity markers (hematological, hepatic, and renal). GA at 50 mg/kg significantly reduced tumor weight and proliferation, decreased Ki-67 and NF-κB expression, increased Bax, reduced Bcl-2, and enhanced cleaved caspase-3, indicating predominant activation of the intrinsic (mitochondrial) apoptotic pathway. Caspase-8 levels remained unchanged. Although 5-FU produced greater tumor inhibition, it induced leukopenia and splenic atrophy, whereas GA preserved hematological, hepatic, and renal parameters. These findings support GA as a promising candidate for adjuvant cancer therapy.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking adaptive oncogenic resistance in glioblastoma via targeting the EGFR-STAT3 axis.","authors":"Nisar Ahmad, Arfan Ullah","doi":"10.1007/s12032-026-03459-4","DOIUrl":"10.1007/s12032-026-03459-4","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains refractory to current targeted therapies. Among the oncogenic pathways implicated in GBM pathogenesis, epidermal growth factor receptor (EGFR) signaling and the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway have emerged as central drivers of tumor growth, immune evasion, and therapeutic resistance. Despite frequent EGFR amplification and mutation, clinical trials targeting EGFR have yielded disappointing outcomes, underscoring the existence of adaptive resistance mechanisms. Accumulating evidence indicated that persistent STAT3 activation represents a critical compensatory node that sustains oncogenic transcriptional programs even when EGFR signaling is pharmacologically inhibited. Here, we propose that the EGFR-STAT3 axis functions not as a linear signaling cascade, but as an adaptive resistance hub that integrates growth factor signaling, inflammatory cytokines, hypoxia, tumor-associated macrophages, and therapeutic stress. This signaling rewiring promotes glioma stemness, metabolic reprogramming, immune suppression, and resistance to chemotherapy and radiotherapy. This review systematically dissects the molecular mechanisms underlying EGFR-STAT3 crosstalk, highlights non-canonical and microenvironment-driven STAT3 activation, explains past therapeutic failures, and evaluates new therapeutic strategies targeting this axis to overcome therapeutic oncogenic adaptive resistance in glioblastoma.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing the genome: role of HUSH complex in retrotransposon regulation and cancer development.","authors":"Hawaida Ahmad, Khadija Tariq, Aqsa Mehreen, Imran Khan Yousafzai, Amina Mahmood, Shaista Aslam, Asma Saleem Qazi, Zaineb Akram, Rida Fatima Saeed","doi":"10.1007/s12032-026-03380-w","DOIUrl":"10.1007/s12032-026-03380-w","url":null,"abstract":"<p><p>Retrotransposons comprise approximately 42% of the human genome and contribute to genomic diversity. Their improper regulation leads to genomic instability and, potentially, cancer. The Human Silencing Hub (HUSH) complex plays a significant role in silencing the genome via epigenetic regulation, specifically through H3K9me3 deposition. Its current identified function is to maintain the genomic stability; however, there is still ambiguity and further study is required about the exact mechanism by which the HUSH complex controls the retrotransposon activity and how its dysfunction contributes to cancer. This systematic review examines genome-wide transcriptional and epigenetic studies whose focus is the role of the HUSH complex in the silencing of retrotransposons and its consequences in cancer. The study also aims to clarify how HUSH complex dysregulation affects gene expression patterns and contributes to tumorigenesis. A comprehensive literature search was conducted through PubMed, ScienceDirect, ProQuest, and Lilac databases, yielding 693 articles. After implementing predefined inclusion and exclusion criteria, 6 studies were selected for analysis. The data extraction from precisely included studies focused on HUSH complex relations with retrotransposons and its effect on cancer-related genes. The study highlights the significant role of the HUSH complex, which efficiently silences retrotransposons like LINE-1 and ERVs, especially by H3K9me3 deposition. Through immune evasion, DNA damage, and retrotransposon reactivation, dysregulation of HUSH components, SETDB1 and MPP8, has been associated with the advancement of cancer. MPP8 knockdown caused differentiation in Acute Myeloid Leukemia (AML), but SETDB1 deletion increased tumor immunogenicity in melanoma. Conclusively, HUSH complex is a key epigenetic regulator of retrotransposons, and its dysfunction contributes to cancer pathogenesis. HUSH components (e.g., SETDB1, MPP8) present, as potential therapeutic and diagnostic biomarkers for different cancers.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of radiotherapy or chemoradiotherapy in older patients with advanced-stage, non-surgically treated head and neck cancer: A machine learning analysis.","authors":"Rasheed Omobolaji Alabi, Alhadi Almangush, Mohammed Elmusrati, Ylva Tiblom Ehrsson, Göran Laurell, Antti A Mäkitie","doi":"10.1007/s12032-026-03420-5","DOIUrl":"10.1007/s12032-026-03420-5","url":null,"abstract":"<p><p>The rising incidence of head and neck squamous cell carcinoma (HNSCC) is linked to both the HPV epidemic and the aging population. As a result, there is an emerging need to develop management strategies for older patients with advanced-stage HNSCC. This study aims to apply machine learning (ML) techniques to compare the effectiveness of definitive concurrent chemoradiotherapy (CRT) and radiotherapy (RT) alone in older patients (≥ 65 years) with stage III-IV non-surgically treated HNSCC. We used Kaplan-Meier (KM) survival curves, Cox proportional hazards models, and ML-based permutation feature importance (PFI) to compare the effectiveness of CRT versus single modality radiotherapy (RT) for disease-specific survival (DSS) in this population of patients with HNSCC. Finally, we used propensity-score matched (PSM) analysis to clarify if there is a significant difference between patients that received either CRT or RT alone. A total of 1525 patients with HNSCC were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program to build the ML model. Furthermore, the PFI analysis evaluated the effectiveness of CRT or RT alone regarding DSS of older (≥ 65 year) patients with HNSCC. Then, we performed a 1:1 propensity-score matched (PSM) analysis to reduce treatment selection bias and to analyze the prognostic role of CRT. Our ML model showed performance accuracy of 55.5% in predicting DSS in this group with HNSCC. The aggregate feature importance showed that treatment option (CRT or RT alone) is among the four most important features for enhancing DSS among these patients. Specifically, our KM curves, Cox proportional hazards model, and PFI analyses all showed that CRT seems more feasible and effective than RT alone for older patients with stage III-IV HNSCC who did not receive surgery. In addition, patients with stage III disease had better survival rates than those with stage IV. The PSM confirmed that there are substantial differences in nearly all covariates between patients who received CRT or RT alone. The results from the SEER database provide insight into a potential survival benefit for CRT in older patients with stage III-IV HNSCC who are not candidates for surgery. This further emphasizes that treatment decisions at an advanced stage may be made according to other patient-related factors rather than chronological (calendar) age alone.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of genetic polymorphisms in xenobiotic-metabolizing enzymes and the risk of oral cancer: a critical review.","authors":"Gabriel Carvalhal de Aguiar, Daniel Vitor de Souza, Barbara Dos Anjos Rosário, Lorrany da Silva Avanci, Antonio Silva, Rogerio Aparecido Dedivitis, Daniel Araki Ribeiro","doi":"10.1007/s12032-026-03428-x","DOIUrl":"10.1007/s12032-026-03428-x","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs) affect many individuals, where exposure to xenobiotics such as tobacco, alcohol, and betel quid is highly prevalent. Inter-individual variability plays a key role regarding genetic polymorphisms in xenobiotic‑metabolizing enzymes. In this study, we searched PubMed, Scopus and Web of Science (up to April 2026) for observational studies and meta‑analyses evaluating CYP1A1, CYP1B1, CYP2E1, GSTM1, GSTT1, GSTP1 and GSTM3 polymorphisms in OSCC and OPMDs. Twenty-one studies met the inclusion criteria. Data on exposures, genotypes and risk estimates were extracted and synthesized qualitatively. Most studies showed that GSTM1 and/or GSTT1 null genotypes are associated with increased risk of OSCC, particularly in Asian cohorts with heavy tobacco and/or betel quid exposure. CYP1A1 and CYP2E1 variants exhibited more heterogeneous results, but several studies indicated elevated risk in smokers, drinkers and betel quid users. Stronger effects consistently appeared in gene-environment interaction models. Polymorphisms in Phase I and Phase II metabolizing enzymes, especially GSTM1/GSTT1 null and selected CYP1A1/CYP2E1 variants, modulate susceptibility to OSCC in exposed individuals, supporting their potential use in risk stratification and targeted prevention strategies.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of siRNA-mediated knockdown of the PD-L1 (CD274) gene on DUSP gene family expression and potential clinical implications in gastric cancer.","authors":"Sinem Uykun, Hakki Coskun, Ayca Tas, Tugba Agbektas, Deniz Sahin Inan, Gülcihan Çinar Kaya, Yavuz Silig","doi":"10.1007/s12032-026-03450-z","DOIUrl":"10.1007/s12032-026-03450-z","url":null,"abstract":"<p><p>This study aimed to investigate the molecular interaction between PD-L1 (CD274) and members of the dual-specificity phosphatase (DUSP) gene family (DUSP1, DUSP2, DUSP4, DUSP6, and DUSP10) in gastric adenocarcinoma (GC) using integrated bioinformatic and experimental approaches. Bioinformatic analyses based on UALCAN, GEPIA, TIMER 2.0, and STRING databases revealed significant dysregulation of PD-L1 (CD274), DUSP2, DUSP4, DUSP6, and DUSP10 in tumor tissues, while DUSP1 was downregulated. Gene expression patterns were associated with tumor stage and patient prognosis. Promoter methylation analyses suggested epigenetic regulation of PD-L1 (CD274), DUSP1, and DUSP2, and copy number variation analysis indicated that gene amplifications were associated with altered immune cell infiltration, particularly dendritic cells and T lymphocytes. Gene expression was further evaluated in gastric tumor and adjacent non-tumor tissues using the GEO dataset GSE27342. Functional validation using siRNA-mediated PD-L1 (CD274) knockdown in AGS gastric cancer cells (GC) resulted in reduced cell viability, induction of apoptosis, upregulation of DUSP4, and downregulation of DUSP2. qPCR analysis of patient-derived tissue samples demonstrated significant alteration of DUSP6 expression, while peripheral blood analysis revealed significant suppression of DUSP2 in GC patients compared to controls. Logistic regression and ROC analyses identified DUSP6 (tissue level) and DUSP2 (blood level) as the most statistically relevant markers among the evaluated genes. Collectively, these findings suggest that PD-L1 (CD274) influences tumor cell survival not only through immune checkpoint signaling but also through modulation of MAPK-associated phosphatases. The coordinated dysregulation of PD-L1 (CD274), DUSP2, and DUSP6 supports the existence of a functional PD-L1/DUSP signaling axis in gastric cancer pathogenesis and highlights its potential relevance for future diagnostic and therapeutic investigations.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A20 promotes OPN ubiquitination and degradation to inhibit cell growth and invasion in human hepatocellular carcinoma.","authors":"Xiangqian Zhang, Zhi Li, Jianyan Qin, Dandan Zhu, Shuhong Zhang, Ye Zhang, Ying Fu, Xiaojin Liu, Qigang Shao","doi":"10.1007/s12032-026-03423-2","DOIUrl":"10.1007/s12032-026-03423-2","url":null,"abstract":"<p><p>Abnormal osteopontin (OPN) expression has been implicated in hepatocellular carcinoma (HCC) progression. In this study, we assessed the prognostic value and biological functions of OPN in HCC. We also identified that A20 interacts with OPN and promotes OPN ubiquitination and protein degradation through the ubiquitin-proteasome system. The reduction in OPN levels induced by A20 attenuates OPN-associated proliferative and migratory phenotypes in HCC cells. Notably, advanced HCC tissues exhibited elevated OPN levels, while A20 expression showed variable patterns in clinical samples. In the clinical cohort, high OPN expression was associated with poorer overall survival, while high A20 expression was also unexpectedly associated with unfavorable prognosis. Combined analysis of OPN and A20 expression provided complementary prognostic stratification for HCC patients. Consequently, our results reveal a mechanism involving OPN ubiquitination and suggest that the OPN/A20 expression profile may provide prognostic stratification for patients after HCC resection. Considering the significance of OPN expression in HCC, our research also provides insights into potential therapeutic strategies for HCC.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated mitochondrial homeostasis disrupted and retrograde signaling activated.","authors":"Pinya Liu, Zihan Wang, Shuhua Xi, Yue Wang","doi":"10.1007/s12032-026-03405-4","DOIUrl":"10.1007/s12032-026-03405-4","url":null,"abstract":"<p><p>This review discusses mitochondrial homeostasis disrupted and retrograde signaling activated in oncogenesis and cancer progression. We summarize mitochondrial alterations and dysfunction in cancer, including mitochondrial DNA mutations, copy number alterations, dynamics changes and abnormalities of mitochondria enzymes in cancer. Furthermore, we discuss the findings on the main molecular mechanisms and roles of mitochondrial retrograde signaling pathways networks, such as reactive oxygen species (ROS), unfolded protein response (mtUPR), calcium and other retrograde signaling on cancer progression. Dysfunctional mitochondria induced retrograde signaling can lead to changes in gene expression. Tumor cells intimidate mitochondrial regulatory pathways to support tumor growth. Looking forward, we highlight critical knowledge gaps, including the need to decipher the spatiotemporal dynamics of retrograde signals, the context‑dependent dual roles of mitochondrial stress responses, and the integration of multi‑omics data to identify predictive biomarkers. We also discuss emerging therapeutic strategies that target mitochondrial retrograde signaling, such as small‑molecule modulators of mitochondrial calcium uniporter, ROS‑scavenging nanomedicines, and combination regimens with immune checkpoint inhibitors. Mitochondrial retrograde signaling might be served as a potential target for new therapeutic interventions in cancers, and future research should focus on translating these mechanistic insights into clinically actionable approaches.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}