Pub Date : 2026-01-22DOI: 10.1016/j.canlet.2026.218269
Sanjib Chaudhary , Muthamil Iniyan Appadurai , Koelina Ganguly , Ramesh Pothuraju , Han-Jun Wang , Jesse L. Cox , Subodh M. Lele , Mohd Wasim Nasser , Imayavaramban Lakshmanan , Muzafar A. Macha , Surinder Kumar Batra , Apar Kishor Ganti
Perineural invasion (PNI) is associated with worse prognosis in various malignancies. Targeting PNI may hinder the tumor metastasis in head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC). We investigated the role of nuclear receptor subfamily 4 group A2 (NR4A2/Nurr1) mediated neuronal invasion in HNSCC and PDAC tumor progression. Aberrant expression of NR4A2 was observed in these tumors, and high levels of NR4A2 were associated with worse survival. The whole genome chromatin immunoprecipitation (ChIP) sequencing with NR4A2 antibody illustrated several genes associated with axonal guidance, suggesting its potential role in PNI. Treatment with conditioned-media (CM) collected from NR4A2-depleted cancer cells showed significantly decreased neurite outgrowths in dorsal root ganglion. Cytokine array analysis revealed several soluble factors, such as CXCL5, CCL2, IGBP2, and TIMP-2, that may be involved in neuritogenesis; these factors are decreased in CM of NR4A2-depleted cells. Further treatment with CXCL5 ligand significantly induced neuritogenesis, while the neurite outgrowth was abrogated when cotreated with CXCR2 (receptor for CXCL5) inhibitor SCH527123. Upregulation of Rac1 and phospho-AKT (S473) downstream signaling of CXCL5 was observed, and the CXCR2 inhibitor abrogated this effect in neuronal cells. Moreover, CM from CXCL5-depleted cells showed reduced neurite length. NR4A2 knockdown in UMSCC1 cells impaired tumor formation in vivo, and the xenograft tissues exhibited significant downregulation of CXCL5, providing direct in vivo evidence for the NR4A2–CXCL5 axis in tumor progression. NR4A2 is a key driver of CXCL5-mediated PNI and the NR4A2/CXCL5/CXCR2 signaling axis is a potential therapeutic target in HNSCC and PDAC.
{"title":"NR4A2 induces perineural invasion in head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma via CXCL5/CXCR2 signaling axis","authors":"Sanjib Chaudhary , Muthamil Iniyan Appadurai , Koelina Ganguly , Ramesh Pothuraju , Han-Jun Wang , Jesse L. Cox , Subodh M. Lele , Mohd Wasim Nasser , Imayavaramban Lakshmanan , Muzafar A. Macha , Surinder Kumar Batra , Apar Kishor Ganti","doi":"10.1016/j.canlet.2026.218269","DOIUrl":"10.1016/j.canlet.2026.218269","url":null,"abstract":"<div><div>Perineural invasion (PNI) is associated with worse prognosis in various malignancies. Targeting PNI may hinder the tumor metastasis in head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC). We investigated the role of nuclear receptor subfamily 4 group A2 (NR4A2/Nurr1) mediated neuronal invasion in HNSCC and PDAC tumor progression. Aberrant expression of NR4A2 was observed in these tumors, and high levels of NR4A2 were associated with worse survival. The whole genome chromatin immunoprecipitation (ChIP) sequencing with NR4A2 antibody illustrated several genes associated with axonal guidance, suggesting its potential role in PNI. Treatment with conditioned-media (CM) collected from NR4A2-depleted cancer cells showed significantly decreased neurite outgrowths in dorsal root ganglion. Cytokine array analysis revealed several soluble factors, such as CXCL5, CCL2, IGBP2, and TIMP-2, that may be involved in neuritogenesis; these factors are decreased in CM of NR4A2-depleted cells. Further treatment with CXCL5 ligand significantly induced neuritogenesis, while the neurite outgrowth was abrogated when cotreated with CXCR2 (receptor for CXCL5) inhibitor SCH527123. Upregulation of Rac1 and phospho-AKT (S473) downstream signaling of CXCL5 was observed, and the CXCR2 inhibitor abrogated this effect in neuronal cells. Moreover, CM from CXCL5-depleted cells showed reduced neurite length. NR4A2 knockdown in UMSCC1 cells impaired tumor formation in vivo, and the xenograft tissues exhibited significant downregulation of CXCL5, providing direct in vivo evidence for the NR4A2–CXCL5 axis in tumor progression. NR4A2 is a key driver of CXCL5-mediated PNI and the NR4A2/CXCL5/CXCR2 signaling axis is a potential therapeutic target in HNSCC and PDAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218269"},"PeriodicalIF":10.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043552","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}
Pub Date : 2026-01-21DOI: 10.1016/j.canlet.2026.218278
Fada Xia , Xudong Zhu , Xiaoyan Li , Qiaoli Yi , Shangjun Zhou , Jiayu Wang , Xia Wang , Kejing Zhang , Cheng Zhan , Hailin Tang , Zhijie Xu , Huiting Zhang , Anli Yang , Yuanliang Yan
Factor-induced gene 4 (FIG4) has been recently identified as a lipid-modifying enzyme that plays an important role in controls autophagolysosomal activity. However, the regulatory mechanisms and biological functions of FIG4 in cancer therapeutic resistance are not well defined. In this study, we identify that FIG4 as a regulator of IL-18 autophagy–lysosomal degradation, participating in the immunotherapy response in triple-negative breast cancer (TNBC). FIG4 overexpression markedly facilitate the autophagy–lysosomal degradation of IL-18 in the LAMP2A-dependent manner. Ubiquitinated IL-18 induced by FIG4 overexpression reduces its secretion, inhibiting the tumor infiltration of immune-suppressive lipid-associated macrophages (LAMs) and re-sensitizing TNBC to immune-checkpoint blockade. Notably, the combination of FIG4 overexpression or IL-18 neutralizing antibody (aIL-18) with PD-1 inhibitor (aPD-1) produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches in TNBC. In conclusion, these findings underscore a novel mechanism underlying the roles of FIG4-IL-18 axis in immunotherapy resistance. Targeting FIG4–IL-18 axis offers a tractable strategy to dismantle LAM-mediated immunotherapy resistance in TNBC.
{"title":"FIG4 downregulation-arrested autophagy-lysosomal degradation of IL-18 drives lipid-associated macrophage polarization and immunotherapy resistance in triple-negative breast cancer","authors":"Fada Xia , Xudong Zhu , Xiaoyan Li , Qiaoli Yi , Shangjun Zhou , Jiayu Wang , Xia Wang , Kejing Zhang , Cheng Zhan , Hailin Tang , Zhijie Xu , Huiting Zhang , Anli Yang , Yuanliang Yan","doi":"10.1016/j.canlet.2026.218278","DOIUrl":"10.1016/j.canlet.2026.218278","url":null,"abstract":"<div><div>Factor-induced gene 4 (FIG4) has been recently identified as a lipid-modifying enzyme that plays an important role in controls autophagolysosomal activity. However, the regulatory mechanisms and biological functions of FIG4 in cancer therapeutic resistance are not well defined. In this study, we identify that FIG4 as a regulator of IL-18 autophagy–lysosomal degradation, participating in the immunotherapy response in triple-negative breast cancer (TNBC). FIG4 overexpression markedly facilitate the autophagy–lysosomal degradation of IL-18 in the LAMP2A-dependent manner. Ubiquitinated IL-18 induced by FIG4 overexpression reduces its secretion, inhibiting the tumor infiltration of immune-suppressive lipid-associated macrophages (LAMs) and re-sensitizing TNBC to immune-checkpoint blockade. Notably, the combination of FIG4 overexpression or IL-18 neutralizing antibody (aIL-18) with PD-1 inhibitor (aPD-1) produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches in TNBC. In conclusion, these findings underscore a novel mechanism underlying the roles of FIG4-IL-18 axis in immunotherapy resistance. Targeting FIG4–IL-18 axis offers a tractable strategy to dismantle LAM-mediated immunotherapy resistance in TNBC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218278"},"PeriodicalIF":10.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040188","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}
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, characterized by complex pathogenesis and limited early diagnostic markers. Multi-omics analyses of mice and patients with primary liver tumors reveal significant depletion of oxidative phosphorylation (OXPHOS), despite increased tumor development. However, how this metabolic reprogramming supports tumor growth remains unclear. Here, we uncover the novel tumor-suppressive function of mitochondrial transcription factor A (TFAM), which is consistently downregulated in human HCC and correlates with poor prognosis. Hepatocyte-specific TFAM depletion promotes hepatocarcinogenesis by enhancing glucose-6-phosphate dehydrogenase (G6PD) activity, the rate-limiting enzyme of pentose phosphate pathway (PPP). Cytosolic TFAM directly binds G6PD and blocks its dimerization, restricting metabolism toward PPP, inhibiting nucleotide biosynthesis and slowing down tumor growth. Genetic or pharmacological inhibition of G6PD with 6-aminonicotinamide (6AN) reverses the tumorigenic effects of TFAM deficiency, highlighting a critical metabolic reprogramming in HCC progression. We further show silent mating type information regulation2 homolog-3 (SIRT3)-mediated deacetylation stabilizes TFAM, whereas SIRT3 downregulation promotes TFAM degradation via polyubiquitination. Together, our study reveals a novel mode of metabolic reprogramming due to the loss of TFAM and identifies the TFAM-G6PD axis as a metabolic vulnerability, offering a promising synthetic lethal therapeutic strategy for liver cancer.
{"title":"Loss of TFAM accelerates pentose phosphate pathway by unleashing G6PD oligomerization to drive hepatocarcinogenesis","authors":"Xiaoxiao Zhu, Wanli Ma, Xiaoying Ji, Jinli He, Jiao Luo, Xiangbing Kong, Honghui Guo, Linran Zhang, Yaxin Ju, Lin Xu, Yuan Jin, Dianke Yu, Kunming Zhao","doi":"10.1016/j.canlet.2026.218275","DOIUrl":"10.1016/j.canlet.2026.218275","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, characterized by complex pathogenesis and limited early diagnostic markers. Multi-omics analyses of mice and patients with primary liver tumors reveal significant depletion of oxidative phosphorylation (OXPHOS), despite increased tumor development. However, how this metabolic reprogramming supports tumor growth remains unclear. Here, we uncover the novel tumor-suppressive function of mitochondrial transcription factor A (TFAM), which is consistently downregulated in human HCC and correlates with poor prognosis. Hepatocyte-specific TFAM depletion promotes hepatocarcinogenesis by enhancing glucose-6-phosphate dehydrogenase (G6PD) activity, the rate-limiting enzyme of pentose phosphate pathway (PPP). Cytosolic TFAM directly binds G6PD and blocks its dimerization, restricting metabolism toward PPP, inhibiting nucleotide biosynthesis and slowing down tumor growth. Genetic or pharmacological inhibition of G6PD with 6-aminonicotinamide (6AN) reverses the tumorigenic effects of TFAM deficiency, highlighting a critical metabolic reprogramming in HCC progression. We further show silent mating type information regulation2 homolog-3 (SIRT3)-mediated deacetylation stabilizes TFAM, whereas SIRT3 downregulation promotes TFAM degradation via polyubiquitination. Together, our study reveals a novel mode of metabolic reprogramming due to the loss of TFAM and identifies the TFAM-G6PD axis as a metabolic vulnerability, offering a promising synthetic lethal therapeutic strategy for liver cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218275"},"PeriodicalIF":10.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040107","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}
Palmitoyltransferase ZDHHC5 (DHHC5) is a palmitoylation regulator that adds palmitate to various protein substrates. Its role in pancreatic cancer (PC) remains unclear, thus posing significant challenges to the promotion of the "cold tumor" immune microenvironment, the development of new drugs, and targeted therapy. In this study, through comprehensive bioinformatics analysis, we determined the association between DHHC5 and various immune and metabolic components which we refer to as post-translational modification checkpoint of palmitoylation (Palm-PTM-checkpoint). We found that in pancreatic cancer, DHHC5 upregulates the palmitoylation of succinate dehydrogenase B (SDHB), stabilizes the SDHB protein, inhibits lysosomal degradation, and increases fumarate production by promoting succinate dehydrogenase activity. This process suppresses the overall immune microenvironment, especially the anti-tumor immunity of T cells. Mechanistically, the excessive fumarate produced by the palmitoylation cycle of SDHB in cancer cells increases the production of acetyl-CoA in T cells and promotes T-cell exhaustion by upregulating the H3K27 acetylation (H3K27ac) -PD1 axis. Additionally, based on the sequence near the palmitoylation site of SDHB, we designed an intracellular penetrating peptide CPP-S1 targeting SDHB palmitoylation. As a competitive inhibitor, CPP-S1 inhibits the palmitoylation modification of SDHB, reduces the SDHB protein level, and suppresses the tumor growth of pancreatic cancer cells, with enhanced effects when used in combination with anti-PD1 therapy. These findings reveal a new strategy to overcome the immune escape mediated by the DHHC5-SDHB axis in pancreatic cancer immunotherapy.
{"title":"Succinate dehydrogenase B palmitoylation promotes T cell exhaustion through the H3K27ac-PD1 axis in pancreatic cancer.","authors":"Fuxin Huang, Cheukfai Li, Yue Chen, Jianmin Lu, Jike Fang, Zhongyan Zhang, Jinhui Wei, Chuanzhao Zhang, Baohua Hou, Shanzhou Huang","doi":"10.1016/j.canlet.2026.218277","DOIUrl":"10.1016/j.canlet.2026.218277","url":null,"abstract":"<p><p>Palmitoyltransferase ZDHHC5 (DHHC5) is a palmitoylation regulator that adds palmitate to various protein substrates. Its role in pancreatic cancer (PC) remains unclear, thus posing significant challenges to the promotion of the \"cold tumor\" immune microenvironment, the development of new drugs, and targeted therapy. In this study, through comprehensive bioinformatics analysis, we determined the association between DHHC5 and various immune and metabolic components which we refer to as post-translational modification checkpoint of palmitoylation (Palm-PTM-checkpoint). We found that in pancreatic cancer, DHHC5 upregulates the palmitoylation of succinate dehydrogenase B (SDHB), stabilizes the SDHB protein, inhibits lysosomal degradation, and increases fumarate production by promoting succinate dehydrogenase activity. This process suppresses the overall immune microenvironment, especially the anti-tumor immunity of T cells. Mechanistically, the excessive fumarate produced by the palmitoylation cycle of SDHB in cancer cells increases the production of acetyl-CoA in T cells and promotes T-cell exhaustion by upregulating the H3K27 acetylation (H3K27ac) -PD1 axis. Additionally, based on the sequence near the palmitoylation site of SDHB, we designed an intracellular penetrating peptide CPP-S1 targeting SDHB palmitoylation. As a competitive inhibitor, CPP-S1 inhibits the palmitoylation modification of SDHB, reduces the SDHB protein level, and suppresses the tumor growth of pancreatic cancer cells, with enhanced effects when used in combination with anti-PD1 therapy. These findings reveal a new strategy to overcome the immune escape mediated by the DHHC5-SDHB axis in pancreatic cancer immunotherapy.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218277"},"PeriodicalIF":10.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040283","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}
Pub Date : 2026-01-20DOI: 10.1016/j.canlet.2026.218271
Yuan Huang , Chen Chen , Mingqiang Su , Wanteng Ye , Shu Wei , Kuangye Long , Yunjie Huang , Haiyong Chen , Zhangfeng Zhong , Lina Hou , Jinge Zhang , Wanlong Tan , Fei Li
Cisplatin-based chemotherapy stands as the first-line treatment for metastatic bladder cancer (BCa), yet only 35 % of patients show initial responsiveness, with resistance commonly developing. Therefore, investigating cisplatin-sensitizing targets is warranted for overcoming resistance. In this study, the transmembrane protein 11 (TMEM11) was explored for its role in mediating cisplatin resistance in BCa. Single-cell and bulk RNA sequencing, together with assay for transposase-accessible chromatin using sequencing were utilized. The analyses revealed that TMEM11 was upregulated in cisplatin-resistant cells and associated with mitochondrial metabolic reprogramming and poor prognosis. Spatial transcriptomics and proteomics further confirmed the spatial co-localization of TMEM11 with metabolic pathways enriched in resistant tumors. Functional experiments demonstrated that TMEM11 inhibited BNIP3-mediated mitophagy and apoptosis, thereby stabilizing mitochondrial function to promote cisplatin resistance. Mechanistically, TMEM11 suppressed BNIP3 and impaired mitophagy flux, leading to enhanced survival of cancer cells under cisplatin stress. In vivo, TMEM11 knockdown reduced tumor growth and sensitized tumors to cisplatin treatment. Furthermore, molecular docking and experimental validation identified Curcumin as a high-affinity TMEM11 inhibitor capable of restoring cisplatin sensitivity. This study uncovered the TMEM11-BNIP3 axis as a novel driver of cisplatin resistance in BCa, and proposed pharmacological targeting of TMEM11 as a precise therapeutic strategy to overcome cisplatin resistance.
{"title":"TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer","authors":"Yuan Huang , Chen Chen , Mingqiang Su , Wanteng Ye , Shu Wei , Kuangye Long , Yunjie Huang , Haiyong Chen , Zhangfeng Zhong , Lina Hou , Jinge Zhang , Wanlong Tan , Fei Li","doi":"10.1016/j.canlet.2026.218271","DOIUrl":"10.1016/j.canlet.2026.218271","url":null,"abstract":"<div><div>Cisplatin-based chemotherapy stands as the first-line treatment for metastatic bladder cancer (BCa), yet only 35 % of patients show initial responsiveness, with resistance commonly developing. Therefore, investigating cisplatin-sensitizing targets is warranted for overcoming resistance. In this study, the transmembrane protein 11 (TMEM11) was explored for its role in mediating cisplatin resistance in BCa. Single-cell and bulk RNA sequencing, together with assay for transposase-accessible chromatin using sequencing were utilized. The analyses revealed that TMEM11 was upregulated in cisplatin-resistant cells and associated with mitochondrial metabolic reprogramming and poor prognosis. Spatial transcriptomics and proteomics further confirmed the spatial co-localization of TMEM11 with metabolic pathways enriched in resistant tumors. Functional experiments demonstrated that TMEM11 inhibited BNIP3-mediated mitophagy and apoptosis, thereby stabilizing mitochondrial function to promote cisplatin resistance. Mechanistically, TMEM11 suppressed BNIP3 and impaired mitophagy flux, leading to enhanced survival of cancer cells under cisplatin stress. In vivo, TMEM11 knockdown reduced tumor growth and sensitized tumors to cisplatin treatment. Furthermore, molecular docking and experimental validation identified Curcumin as a high-affinity TMEM11 inhibitor capable of restoring cisplatin sensitivity. This study uncovered the TMEM11-BNIP3 axis as a novel driver of cisplatin resistance in BCa, and proposed pharmacological targeting of TMEM11 as a precise therapeutic strategy to overcome cisplatin resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218271"},"PeriodicalIF":10.1,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015797","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}
Pub Date : 2026-01-20DOI: 10.1016/j.canlet.2026.218258
Hareesh B. Nair , Ajay Nair , Ya-Guang Liu , Dileep K. Vijayan , Ramadevi Subramani , Rajkumar Lakshmanaswamy , Suryavathi Viswanadhapalli , Gangadhara R. Sareddy , Surinder K. Batra , Ratna K. Vadlamudi
Midkine (MDK) is an oncofetal, heparin-binding cytokine that is re-expressed across diverse cancers and correlates with aggressive disease and treatment resistance. This review synthesizes current evidence on MDK as a coordinator of tumor-intrinsic signaling and microenvironmental remodeling. We summarize MDK structural features, extracellular matrix interactions, and receptor systems that mediate MDK signaling, highlighting LRP1 and PTPRZ1 with context-dependent participation of ALK, nucleolin and integrins. Downstream, MDK engages MAPK, PI3K-AKT, STAT3 and NF-κB pathways to promote tumor cell survival, epithelial-mesenchymal plasticity, and therapeutic stress tolerance. We then focus on tumor microenvironment (TME) programs shaped by MDK, including angiogenesis, fibroblast activation and extracellular matrix remodeling, and the establishment of immunosuppressive niches. Across tumor types, MDK is linked to impaired dendritic-cell function, polarization of tumor-associated macrophages, accrual of myeloid-derived suppressor cells and reduced CD8+ T-cell cytotoxic fitness. Finally, we review translational opportunities and challenges, including candidate biomarkers (tumor MDK by IHC/RNA and circulating MDK by ELISA) and rational combination strategies that pair MDK blockade with MAPK-pathway inhibitors or PD-1/PD-L1 immunotherapy. Collectively, these data position MDK as a tractable node connecting tumor-intrinsic signaling with stromal and immune regulation.
{"title":"Midkine (MDK) as a central regulator of the tumor microenvironment: From developmental cytokine to therapeutic target","authors":"Hareesh B. Nair , Ajay Nair , Ya-Guang Liu , Dileep K. Vijayan , Ramadevi Subramani , Rajkumar Lakshmanaswamy , Suryavathi Viswanadhapalli , Gangadhara R. Sareddy , Surinder K. Batra , Ratna K. Vadlamudi","doi":"10.1016/j.canlet.2026.218258","DOIUrl":"10.1016/j.canlet.2026.218258","url":null,"abstract":"<div><div>Midkine (MDK) is an oncofetal, heparin-binding cytokine that is re-expressed across diverse cancers and correlates with aggressive disease and treatment resistance. This review synthesizes current evidence on MDK as a coordinator of tumor-intrinsic signaling and microenvironmental remodeling. We summarize MDK structural features, extracellular matrix interactions, and receptor systems that mediate MDK signaling, highlighting LRP1 and PTPRZ1 with context-dependent participation of ALK, nucleolin and integrins. Downstream, MDK engages MAPK, PI3K-AKT, STAT3 and NF-κB pathways to promote tumor cell survival, epithelial-mesenchymal plasticity, and therapeutic stress tolerance. We then focus on tumor microenvironment (TME) programs shaped by MDK, including angiogenesis, fibroblast activation and extracellular matrix remodeling, and the establishment of immunosuppressive niches. Across tumor types, MDK is linked to impaired dendritic-cell function, polarization of tumor-associated macrophages, accrual of myeloid-derived suppressor cells and reduced CD8<sup>+</sup> T-cell cytotoxic fitness. Finally, we review translational opportunities and challenges, including candidate biomarkers (tumor MDK by IHC/RNA and circulating MDK by ELISA) and rational combination strategies that pair MDK blockade with MAPK-pathway inhibitors or PD-1/PD-L1 immunotherapy. Collectively, these data position MDK as a tractable node connecting tumor-intrinsic signaling with stromal and immune regulation.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218258"},"PeriodicalIF":10.1,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028381","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}
Pub Date : 2026-01-19DOI: 10.1016/j.canlet.2026.218252
Huan Wang , Yunguang Li , Shijie Tang , Yikai Li , Yehan Zhang , Xiaoyi Yin , Juan He , Yiqin Zhu , Yi Zhang , Xiaohan Shi , Maoyuan Sun , Suizhi Gao , Bo Li , Lingyu Zhu , Shuai Yuan , Yaqi Pan , Meilong Shi , Penghao Li , Chuanqi Teng , Chaoliang Zhong , Gang Jin
Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to intrinsic and acquired chemotherapy resistance, particularly after neoadjuvant therapy (NAT). To uncover therapy-induced vulnerabilities, we established matched patient-derived organoids from PDAC tissues obtained before and after NAT, creating a unique platform to track treatment-driven evolution. Comparative analysis of these organoids revealed negligible variation in key driver gene mutations but identified a transition from classical to basal-like subtype in one patient after neoadjuvant therapy. Notably, albumin-bound paclitaxel and gemcitabine (AG) treatment induced the resistance to paclitaxel, accompanied by elevated KRAS and MAPK signaling, which was confirmed by transcriptomic comparison of PDAC patient samples with (30 cases) and without (60 cases) AG treatment. Single-cell RNA sequencing of the organoid-derived xenografts revealed AG treatment promoted the emergence of resistant cell clusters characterized by KRAS and MAPK signaling activation. Importantly, EGFR/KRAS/BRAF signaling inhibitors effectively suppressed the growth of AG-resistant PDAC organoids. In a validation cohort of 29 organoids, pan-KRAS inhibitors exhibited superior efficacy against the residual organoids after AG treatment. These results provided insights into molecular changes in PDAC during treatment process and demonstrate that AG chemotherapy can activate the KRAS and MAPK signaling, presenting a potential target for therapeutic intervention.
{"title":"The vulnerabilities of chemotherapy resistant pancreatic cancer revealed by organoids of pre- and post-neoadjuvant therapy","authors":"Huan Wang , Yunguang Li , Shijie Tang , Yikai Li , Yehan Zhang , Xiaoyi Yin , Juan He , Yiqin Zhu , Yi Zhang , Xiaohan Shi , Maoyuan Sun , Suizhi Gao , Bo Li , Lingyu Zhu , Shuai Yuan , Yaqi Pan , Meilong Shi , Penghao Li , Chuanqi Teng , Chaoliang Zhong , Gang Jin","doi":"10.1016/j.canlet.2026.218252","DOIUrl":"10.1016/j.canlet.2026.218252","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to intrinsic and acquired chemotherapy resistance, particularly after neoadjuvant therapy (NAT). To uncover therapy-induced vulnerabilities, we established matched patient-derived organoids from PDAC tissues obtained before and after NAT, creating a unique platform to track treatment-driven evolution. Comparative analysis of these organoids revealed negligible variation in key driver gene mutations but identified a transition from classical to basal-like subtype in one patient after neoadjuvant therapy. Notably, albumin-bound paclitaxel and gemcitabine (AG) treatment induced the resistance to paclitaxel, accompanied by elevated KRAS and MAPK signaling, which was confirmed by transcriptomic comparison of PDAC patient samples with (30 cases) and without (60 cases) AG treatment. Single-cell RNA sequencing of the organoid-derived xenografts revealed AG treatment promoted the emergence of resistant cell clusters characterized by KRAS and MAPK signaling activation. Importantly, EGFR/KRAS/BRAF signaling inhibitors effectively suppressed the growth of AG-resistant PDAC organoids. In a validation cohort of 29 organoids, pan-KRAS inhibitors exhibited superior efficacy against the residual organoids after AG treatment. These results provided insights into molecular changes in PDAC during treatment process and demonstrate that AG chemotherapy can activate the KRAS and MAPK signaling, presenting a potential target for therapeutic intervention.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218252"},"PeriodicalIF":10.1,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017541","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}
Pub Date : 2026-01-17DOI: 10.1016/j.canlet.2026.218259
Yaning Yang , Chengming Liu , Lu Yang , Sufei Zheng , Haiyan Xu , Shuyang Zhang , Linyan Tian , Nan Sun , Jie He , Yan Wang
Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, we retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression or inhibition and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P = 0.001) and OS (median: 15.63 vs. 32.80 months, P = 0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR = 2.42, P < 0.001) and OS (HR = 2.96, P < 0.001) and was correlated with progressive disease (PD, P = 0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8+ T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8+ T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.
一线化学免疫治疗的原发性耐药仍然是晚期非小细胞肺癌（NSCLC）治疗的一个重大挑战。尽管白细胞介素-6 （IL-6）等细胞因子与免疫检查点抑制剂（ICI）单一疗法的耐药性有关，但它们对化学免疫治疗结果的预测价值和潜在机制尚不明确。本研究探讨血浆IL-6基线水平对非小细胞肺癌预后的意义及其在肿瘤免疫微环境（TIME）形成中的作用。在这里，我们回顾性分析了123例接受抗pd -1抑制剂加化疗治疗的晚期非小细胞肺癌患者的数据。ELISA法测定血浆IL-6基线水平。通过Kaplan-Meier和Cox回归分析评估无进展生存期（PFS）和总生存期（OS）。我们建立IL-6过表达（IL6a）或抑制（IL6i）的小鼠肺腺癌（LLC）和鳞状细胞癌（KLN205）模型，并采用抗pd -1治疗±化疗。监测肿瘤生长情况，并对肿瘤浸润免疫细胞进行单细胞RNA测序（scRNA-seq）。结果显示，高基线血浆IL-6水平（>7.002 pg/mL）患者的PFS（中位数：7.20 vs. 16.63个月，P=0.001）和OS（中位数：15.63 vs. 32.80个月，P=0.001）明显低于低基线水平患者。高IL-6水平是PFS恶化的独立预测因子（HR=2.42， P+ t细胞，同时增加调节性t细胞（Tregs）的比例）。相反，IL-6抑制促进了免疫刺激的巨噬细胞表型（以Ccl8表达增加为特征），增强了CD8+ t细胞的浸润和功能。高IL-6水平也与NK细胞脱颗粒通路的损伤相关。这些研究结果表明，血浆IL-6基线水平升高是接受一线化疗免疫治疗的晚期NSCLC患者原发性耐药和生存不良的可靠独立预测因子。从机制上讲，IL-6通过促进原肿瘤巨噬细胞极化来驱动免疫抑制TIME的形成。这反过来又抑制细胞毒性T细胞浸润，促进Treg扩增，损害NK细胞功能，表明靶向IL-6代表了克服化学免疫治疗耐药的有希望的策略。
{"title":"IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function","authors":"Yaning Yang , Chengming Liu , Lu Yang , Sufei Zheng , Haiyan Xu , Shuyang Zhang , Linyan Tian , Nan Sun , Jie He , Yan Wang","doi":"10.1016/j.canlet.2026.218259","DOIUrl":"10.1016/j.canlet.2026.218259","url":null,"abstract":"<div><div>Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, we retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression or inhibition and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P = 0.001) and OS (median: 15.63 vs. 32.80 months, P = 0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR = 2.42, P < 0.001) and OS (HR = 2.96, P < 0.001) and was correlated with progressive disease (PD, P = 0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8<sup>+</sup> T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8<sup>+</sup> T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218259"},"PeriodicalIF":10.1,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003281","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}
Pub Date : 2026-01-16DOI: 10.1016/j.canlet.2026.218260
Kasey R. Cargill , Noah M. Feder , Tyler Wilhite , Walid F. Gellad , Heath D. Skinner , Yvonne M. Mowery , Christopher T. Wilke
{"title":"Price transparency compliance and variation for proton therapy in the United States","authors":"Kasey R. Cargill , Noah M. Feder , Tyler Wilhite , Walid F. Gellad , Heath D. Skinner , Yvonne M. Mowery , Christopher T. Wilke","doi":"10.1016/j.canlet.2026.218260","DOIUrl":"10.1016/j.canlet.2026.218260","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218260"},"PeriodicalIF":10.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997363","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}
Pub Date : 2026-01-14DOI: 10.1016/j.canlet.2026.218256
Yueqin Diao , Xiao Chen , Ziyan Huang , Qian Tan , Meng Yang , Hanyi Yu , Yanwu Xu , Xing Hu
The rapid development of multimodal large language models (LLMs) such as GPT and Med-PaLM is reshaping medical practice. Skin cancer, one of the most prevalent malignancies, encompasses diverse subtypes and early signs that often resemble benign lesions, making timely detection and accurate diagnosis challenging. Traditional diagnostic methods are hindered by subjectivity, sampling bias, and low efficiency. Skin cancer diagnosis is largely constrained by strong subjectivity, sampling bias, and low diagnostic efficiency regularly. Although immunotherapy and targeted therapy aimed at the tumor microenvironment have brought new therapeutic possibilities to patients, tumor heterogeneity and immune evasion remain major unresolved challenges. Artificial intelligence techniques based on deep learning and complex neural networks can integrate dermoscopic images, histopathological information, and genetic databases through multimodal fusion strategies, enabling the extraction of richer and complementary features and thereby significantly improving diagnostic accuracy and robustness. Moreover, tailoring treatment strategies according to individual patient characteristics facilitates truly personalized therapy and prognostic assessment. In the field of drug development, artificial intelligence accelerates the screening and simulation of candidate compounds, substantially reducing development time and expenditure. This review summarizes recent advances in AI for skin cancer, with emphasis on early detection, individualized therapy, and patient management. We further discuss challenges related to data quality and model interpretability, emphasizing the importance of dermatology-specific foundation models and collaboration between clinicians and engineers.
{"title":"Cutting-edge AI technologies in skin cancer applications","authors":"Yueqin Diao , Xiao Chen , Ziyan Huang , Qian Tan , Meng Yang , Hanyi Yu , Yanwu Xu , Xing Hu","doi":"10.1016/j.canlet.2026.218256","DOIUrl":"10.1016/j.canlet.2026.218256","url":null,"abstract":"<div><div>The rapid development of multimodal large language models (LLMs) such as GPT and Med-PaLM is reshaping medical practice. Skin cancer, one of the most prevalent malignancies, encompasses diverse subtypes and early signs that often resemble benign lesions, making timely detection and accurate diagnosis challenging. Traditional diagnostic methods are hindered by subjectivity, sampling bias, and low efficiency. Skin cancer diagnosis is largely constrained by strong subjectivity, sampling bias, and low diagnostic efficiency regularly. Although immunotherapy and targeted therapy aimed at the tumor microenvironment have brought new therapeutic possibilities to patients, tumor heterogeneity and immune evasion remain major unresolved challenges. Artificial intelligence techniques based on deep learning and complex neural networks can integrate dermoscopic images, histopathological information, and genetic databases through multimodal fusion strategies, enabling the extraction of richer and complementary features and thereby significantly improving diagnostic accuracy and robustness. Moreover, tailoring treatment strategies according to individual patient characteristics facilitates truly personalized therapy and prognostic assessment. In the field of drug development, artificial intelligence accelerates the screening and simulation of candidate compounds, substantially reducing development time and expenditure. This review summarizes recent advances in AI for skin cancer, with emphasis on early detection, individualized therapy, and patient management. We further discuss challenges related to data quality and model interpretability, emphasizing the importance of dermatology-specific foundation models and collaboration between clinicians and engineers<strong>.</strong></div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218256"},"PeriodicalIF":10.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988121","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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