Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) axis can induce durable tumor regression in a subset of NSCLC patients; however, most exhibit resistance to ICIs therapy. Here, we identify the protein kinase Cι (PKCι)) as a biomarker and critical mediator of poor ICIs responsiveness in NSCLC. High PKCι expression correlates with resistance to anti-PD-1 antibody (αPD1) therapy, whereas low PKCι expression are highly sensitive. PKCι-dependent resistance to αPD1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, PKCι regulated Yap1-dependent transcription of CCL7, which recruits TAMs and fosters an immunosuppressive microenvironment. In contrast, Overexpression of PKCι or CCL7 in PKCι-knockdown tumors restores TAMs infiltration and αPD1 resistance. Pharmacological inhibition of PKCι with auranofin (AF) reduces TAMs accumulation and promotes CD8+T cell infiltration by inhibiting the PKCι-Yap1-CCL7 axis. Combination therapy with AF and αPD1 triggers a CD8+T cell-dependent antitumor immune response, thereby controlling tumor growth in situ or subcutaneously. In summary, our study reveals a PKCι-mediated immunosuppressive pathway driving ICIs resistance and support PKCι inhibition as a promising strategy to enhance immunotherapy efficacy in NSCLC.
{"title":"Protein kinase Cι-driven macrophage infiltration mediates immunosuppression in non-small cell lung cancer","authors":"Shichuan Hu , Zichen Zhao , Jing Zhao , Yilin Liang , Lingye Zeng , Yifei Xia , Haoya Guo , Lili Jiang , Yan Zhang","doi":"10.1016/j.canlet.2026.218330","DOIUrl":"10.1016/j.canlet.2026.218330","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) axis can induce durable tumor regression in a subset of NSCLC patients; however, most exhibit resistance to ICIs therapy. Here, we identify the protein kinase Cι (PKCι)) as a biomarker and critical mediator of poor ICIs responsiveness in NSCLC. High PKCι expression correlates with resistance to anti-PD-1 antibody (αPD1) therapy, whereas low PKCι expression are highly sensitive. PKCι-dependent resistance to αPD1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, PKCι regulated Yap1-dependent transcription of CCL7, which recruits TAMs and fosters an immunosuppressive microenvironment. In contrast, Overexpression of PKCι or CCL7 in PKCι-knockdown tumors restores TAMs infiltration and αPD1 resistance. Pharmacological inhibition of PKCι with auranofin (AF) reduces TAMs accumulation and promotes CD8+T cell infiltration by inhibiting the PKCι-Yap1-CCL7 axis. Combination therapy with AF and αPD1 triggers a CD8+T cell-dependent antitumor immune response, thereby controlling tumor growth in situ or subcutaneously. In summary, our study reveals a PKCι-mediated immunosuppressive pathway driving ICIs resistance and support PKCι inhibition as a promising strategy to enhance immunotherapy efficacy in NSCLC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218330"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257643","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 : 2026-04-28Epub Date: 2026-02-25DOI: 10.1016/j.canlet.2026.218346
Murray Korc , Min Li
{"title":"Why immunotherapy fails in immune-cold tumors: A systems framework from immune baseline to designable immune remodeling","authors":"Murray Korc , Min Li","doi":"10.1016/j.canlet.2026.218346","DOIUrl":"10.1016/j.canlet.2026.218346","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218346"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316161","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 : 2026-04-28Epub Date: 2026-02-07DOI: 10.1016/j.canlet.2026.218308
Mei Luo , Shiyu Wu , Chenxin Huang , Ziyuan Zheng , Qiaoxi Xia , Yonghua Li , Xiao Zhou , Shihong Hong , Ronghui Zhong , Weijie Li , Botao Wang , Shi-Yuan Cheng , Xiaobing Jiang , Junjun Li , Tianzhi Huang
The hyperactivation of the transcriptional coactivator YAP, a downstream effector of the Hippo pathway, has been implicated in the initiation and progression of human cancers including glioblastoma (GBM), but the underlying mechanisms remain elusive. In this study, we demonstrate that methionine promotes YAP activation through PRMT5-mediated symmetrical dimethylation (sDMA) at a conserved arginine residue within five conserved LATS-targeting motifs (HXRXXS), with R124 identified as the primary site of modification. R124 sDMA (R124me2s) serves as a physiological protective mechanism against LATS-mediated inhibitory phosphorylation of YAP at Ser127, thereby facilitating YAP nuclear translocation and enhancing its transcriptional activity. Moreover, YAP R124 sDMA drives tumor methionine addiction and tumorigenicity of GBM through a feedforward loop in which YAP transcriptionally upregulates PRMT5 and the methionine transporters SLC3A2/SLC7A5. Furthermore, radiation activates PRMT5-YAP-SLC3A2/7A5 axis to promote GBM cell survival. Inhibiting this signaling axis in combination with radiotherapy impairs intracranial xenograft growth, resulting in significant survival extensions for treated animals. Overall, our findings uncover a previously unrecognized regulatory axis where PRMT5-mediated R124me2s governs YAP activation through a feedback mechanism, presenting novel therapeutic vulnerabilities in GBM.
{"title":"Inhibition of PRMT5-dependent YAP methylation attenuates tumorigenicity and radioresistance in glioblastoma","authors":"Mei Luo , Shiyu Wu , Chenxin Huang , Ziyuan Zheng , Qiaoxi Xia , Yonghua Li , Xiao Zhou , Shihong Hong , Ronghui Zhong , Weijie Li , Botao Wang , Shi-Yuan Cheng , Xiaobing Jiang , Junjun Li , Tianzhi Huang","doi":"10.1016/j.canlet.2026.218308","DOIUrl":"10.1016/j.canlet.2026.218308","url":null,"abstract":"<div><div>The hyperactivation of the transcriptional coactivator YAP, a downstream effector of the Hippo pathway, has been implicated in the initiation and progression of human cancers including glioblastoma (GBM), but the underlying mechanisms remain elusive. In this study, we demonstrate that methionine promotes YAP activation through PRMT5-mediated symmetrical dimethylation (sDMA) at a conserved arginine residue within five conserved LATS-targeting motifs (HXRXXS), with R124 identified as the primary site of modification. R124 sDMA (R124me2s) serves as a physiological protective mechanism against LATS-mediated inhibitory phosphorylation of YAP at Ser127, thereby facilitating YAP nuclear translocation and enhancing its transcriptional activity. Moreover, YAP R124 sDMA drives tumor methionine addiction and tumorigenicity of GBM through a feedforward loop in which YAP transcriptionally upregulates PRMT5 and the methionine transporters SLC3A2/SLC7A5. Furthermore, radiation activates PRMT5-YAP-SLC3A2/7A5 axis to promote GBM cell survival. Inhibiting this signaling axis in combination with radiotherapy impairs intracranial xenograft growth, resulting in significant survival extensions for treated animals. Overall, our findings uncover a previously unrecognized regulatory axis where PRMT5-mediated R124me2s governs YAP activation through a feedback mechanism, presenting novel therapeutic vulnerabilities in GBM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218308"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149247","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 : 2026-04-28Epub Date: 2026-02-15DOI: 10.1016/j.canlet.2026.218326
Zhong Xie , Shaojie Li , Jie Yang , Zhengpeng Zhang , Shuren Li , Chuandong Lang , Mingxing Yang , Bin Wang , Xiaowei Yu , Zhihong Li , Yijun Kang , Chi Yin , Qing Yang
Advanced prostate cancer (PCa) frequently metastasizes to bone, where the immunosuppressive tumor microenvironment (TME) limits immune checkpoint blockade (ICB) efficacy. Nevertheless, the molecular mechanisms underlying this immunosuppressive bone TME and bone metastasis (BM) are not yet fully understood. Analysis of clinical PCa samples, employing in situ hybridization, RT-qPCR, and bioinformatics, demonstrated a progressive downregulation of lncRNA SNHG18 throughout PCa progression, with the lowest expression levels observed in BM associated with poor prognosis. We demonstrate that the downregulation of SNHG18 contributes to castration-resistant prostate cancer (CRPC) and BM development by utilizing an androgen-independent Myc-CaP subline, derived from Androgen receptor positive (AR+) Myc-CaP cells through chronic steroid deprivation, alongside in vitro and in vivo models. SNHG18 alters the bone microenvironment through the reprogramming of arginine metabolism. Deficiency of SNHG18 resulted in the upregulation of ARG2 and NOS2, which caused arginine depletion, enhanced infiltration of immunosuppressive cells, and compromised effector T-cell function. Mechanistically, SNHG18 bound to YBX1 and recruited TRIM21 to induce YBX1 degradation, thereby inhibiting YBX1-mediated transcriptional activation of NOS2 and ARG2. Therapeutically, SNHG18 overexpression enhanced anti-PD-1 therapy efficacy in murine BM models. Consequently, SNHG18 deficiency fosters an immunosuppressive TME and promotes PCa BM. SNHG18 expression may serve as a predictive biomarker for ICB response, offering a novel strategy to overcome immunotherapy resistance in PCa BM.
{"title":"SNHG18 deficiency reprograms arginine metabolism to foster an immunosuppressive microenvironment in prostate cancer bone metastasis","authors":"Zhong Xie , Shaojie Li , Jie Yang , Zhengpeng Zhang , Shuren Li , Chuandong Lang , Mingxing Yang , Bin Wang , Xiaowei Yu , Zhihong Li , Yijun Kang , Chi Yin , Qing Yang","doi":"10.1016/j.canlet.2026.218326","DOIUrl":"10.1016/j.canlet.2026.218326","url":null,"abstract":"<div><div>Advanced prostate cancer (PCa) frequently metastasizes to bone, where the immunosuppressive tumor microenvironment (TME) limits immune checkpoint blockade (ICB) efficacy. Nevertheless, the molecular mechanisms underlying this immunosuppressive bone TME and bone metastasis (BM) are not yet fully understood. Analysis of clinical PCa samples, employing in situ hybridization, RT-qPCR, and bioinformatics, demonstrated a progressive downregulation of lncRNA SNHG18 throughout PCa progression, with the lowest expression levels observed in BM associated with poor prognosis. We demonstrate that the downregulation of SNHG18 contributes to castration-resistant prostate cancer (CRPC) and BM development by utilizing an androgen-independent Myc-CaP subline, derived from Androgen receptor positive (AR<sup>+</sup>) Myc-CaP cells through chronic steroid deprivation, alongside in vitro and in vivo models. SNHG18 alters the bone microenvironment through the reprogramming of arginine metabolism. Deficiency of SNHG18 resulted in the upregulation of ARG2 and NOS2, which caused arginine depletion, enhanced infiltration of immunosuppressive cells, and compromised effector T-cell function. Mechanistically, SNHG18 bound to YBX1 and recruited TRIM21 to induce YBX1 degradation, thereby inhibiting YBX1-mediated transcriptional activation of NOS2 and ARG2. Therapeutically, SNHG18 overexpression enhanced anti-PD-1 therapy efficacy in murine BM models. Consequently, SNHG18 deficiency fosters an immunosuppressive TME and promotes PCa BM. SNHG18 expression may serve as a predictive biomarker for ICB response, offering a novel strategy to overcome immunotherapy resistance in PCa BM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218326"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212177","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 : 2026-04-28Epub Date: 2026-02-12DOI: 10.1016/j.canlet.2026.218320
Keisuke Shigeta , Shinkichi Takamori , Hiroki Ozawa , Naoki Haratake , Mai Onishi , Tatsuaki Daimon , Tomohiro Kitano , Atrayee Bhattacharya , Atsushi Fushimi , Mototsugu Oya , Mark D. Long , Donald Kufe
Advanced castration-resistant prostate cancer (CRPC) is responsive to PARP inhibitors, but only in settings of defects in homologous recombination (HR). The oncogenic M1C protein drives CRPC progression; however, it is not known if M1C plays a role in the response to PARP inhibition. The present work demonstrates that M1C is induced by olaparib treatment of HR-competent CRPC cells. As a result, M1C drives (i) ATM expression, (ii) phosphorylation of KAP1(S824) and (iii) activation of STING, which have been linked to derepression of the LINE-1 (L1) retrotransposon. In this way, M1C is necessary for induction of (i) L1-5′UTR, L1-ORF1 and L1-ORF2 transcripts and (ii) the encoded ORF1p RNA binding protein. Activation of retrotransposons induces genomic instability and drug resistance. By extension, we show that M1C also activates HERV-K102/108 gag, pol and env genes and expression of the HERV-K ENV protein. Our work further demonstrates that M1C integrates L1 and HERV-K activation with induction of APOBEC3 (A3) genes that evolved to restrain genomic instability induced by these retrotransposons. Of translational relevance, these findings demonstrate that M1C (i) is essential for inducing L1, HERV-K and A3 expression and resistance of CRPC cells to olaparib, and (ii) is a target for advancing the treatment of HR-competent CRPC with PARP inhibitors.
{"title":"M1C mediates LINE-1 transcription in PARP inhibitor-treated prostate cancer cells","authors":"Keisuke Shigeta , Shinkichi Takamori , Hiroki Ozawa , Naoki Haratake , Mai Onishi , Tatsuaki Daimon , Tomohiro Kitano , Atrayee Bhattacharya , Atsushi Fushimi , Mototsugu Oya , Mark D. Long , Donald Kufe","doi":"10.1016/j.canlet.2026.218320","DOIUrl":"10.1016/j.canlet.2026.218320","url":null,"abstract":"<div><div>Advanced castration-resistant prostate cancer (CRPC) is responsive to PARP inhibitors, but only in settings of defects in homologous recombination (HR). The oncogenic M1C protein drives CRPC progression; however, it is not known if M1C plays a role in the response to PARP inhibition. The present work demonstrates that M1C is induced by olaparib treatment of HR-competent CRPC cells. As a result, M1C drives (i) ATM expression, (ii) phosphorylation of KAP1(S824) and (iii) activation of STING, which have been linked to derepression of the LINE-1 (L1) retrotransposon. In this way, M1C is necessary for induction of (i) L1-5′UTR, L1-ORF1 and L1-ORF2 transcripts and (ii) the encoded ORF1p RNA binding protein. Activation of retrotransposons induces genomic instability and drug resistance. By extension, we show that M1C also activates HERV-K102/108 gag, pol and env genes and expression of the HERV-K ENV protein. Our work further demonstrates that M1C integrates L1 and HERV-K activation with induction of APOBEC3 (A3) genes that evolved to restrain genomic instability induced by these retrotransposons. Of translational relevance, these findings demonstrate that M1C (i) is essential for inducing L1, HERV-K and A3 expression and resistance of CRPC cells to olaparib, and (ii) is a target for advancing the treatment of HR-competent CRPC with PARP inhibitors.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218320"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197526","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 : 2026-04-28Epub Date: 2026-02-17DOI: 10.1016/j.canlet.2026.218331
Shaobo Zhang , Yuanyuan Guo , Haoran Qi , Mengyao Wu , Yumeng Hu , Gaoyuan Lv , Yuxin Ye , Jing Han , Qiong Zeng , Yueran Du , Binghe Xu , Mingyang Liu
Pancreatic cancer remains one of the deadliest malignancies, characterized as a natural “immune desert”. Despite the remarkable advances of cancer immunotherapy in recent years, it shows minimal efficacy in this cancer type. Cancer-associated fibroblasts (CAFs) play a crucial role in pancreatic cancer progression and immune regulation. Although their clinical potential has garnered significant attention, their specific functions and underlying mechanisms remain poorly defined. Here, we elucidate a mechanism by which CAFs reprogram PC cells to suppress CD8+ T cells. We found that CAFs enhance the CD8+ T cell-suppressive function of PC cells in vitro, and CAFs drive tumor progression by reduced and dysfunctional CD8+ T cells in vivo. Mechanistically, CAF-derived miR-181b-5p targets SEC24C (a key transporter for the STING) in PC cells to inhibit the STING phosphorylation. The inhibition of STING phosphorylation blocks YY1 nuclear translocation, thereby de-repressing SUSD2 and LGALS1 transcription. The upregulated LGALS1 is then secreted via SUSD2 assistance, ultimately suppressing CD8+ T cell function and inducing apoptosis. Our findings define a stromal–immune axis in pancreatic cancer, linking miR-181b-5p from CAFs to the establishment of an immune-suppressive niche via the STING pathway in tumor cells, thereby revealing this cascade as a targetable mechanism to counteract immune evasion.
{"title":"Cancer-associated fibroblasts promote immune evasion in pancreatic cancer via miR-181b-5p/STING/LGALS1 pathway","authors":"Shaobo Zhang , Yuanyuan Guo , Haoran Qi , Mengyao Wu , Yumeng Hu , Gaoyuan Lv , Yuxin Ye , Jing Han , Qiong Zeng , Yueran Du , Binghe Xu , Mingyang Liu","doi":"10.1016/j.canlet.2026.218331","DOIUrl":"10.1016/j.canlet.2026.218331","url":null,"abstract":"<div><div>Pancreatic cancer remains one of the deadliest malignancies, characterized as a natural “immune desert”. Despite the remarkable advances of cancer immunotherapy in recent years, it shows minimal efficacy in this cancer type. Cancer-associated fibroblasts (CAFs) play a crucial role in pancreatic cancer progression and immune regulation. Although their clinical potential has garnered significant attention, their specific functions and underlying mechanisms remain poorly defined. Here, we elucidate a mechanism by which CAFs reprogram PC cells to suppress CD8<sup>+</sup> T cells. We found that CAFs enhance the CD8<sup>+</sup> T cell-suppressive function of PC cells <em>in vitro</em>, and CAFs drive tumor progression by reduced and dysfunctional CD8<sup>+</sup> T cells <em>in vivo</em>. Mechanistically, CAF-derived miR-181b-5p targets SEC24C (a key transporter for the STING) in PC cells to inhibit the STING phosphorylation. The inhibition of STING phosphorylation blocks YY1 nuclear translocation, thereby de-repressing SUSD2 and LGALS1 transcription. The upregulated LGALS1 is then secreted via SUSD2 assistance, ultimately suppressing CD8<sup>+</sup> T cell function and inducing apoptosis. Our findings define a stromal–immune axis in pancreatic cancer, linking miR-181b-5p from CAFs to the establishment of an immune-suppressive niche via the STING pathway in tumor cells, thereby revealing this cascade as a targetable mechanism to counteract immune evasion.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218331"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225620","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}
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that has a poor survival rate of ∼13 % with limited options for effective therapies. DDX3 is a member of the DEAD-box RNA helicase enzyme family. It acts as an adapter protein that interacts with several transcription factors, enhancing their binding ability to the promoters of genes involved in cancer progression. Previously, we demonstrated that PAF1, a component of the RNA polymerase II-associated factor 1 complex, interacts with DDX3 to promote PDAC stemness. Here, we investigated the therapeutic efficacy of RK-33, a small-molecule inhibitor targeting DDX3, in combination with gemcitabine (GEM) and 5-fluorouracil (5FU), which enhanced therapeutic efficacy in KRAS-driven PDAC.-DDX3 and PAF1 exhibit progressively increased expression in various stages and correlate well with poor survival of PDAC. Targeting DDX3/PAF1 significantly mitigated clonogenic, EMT, and stemness phenotypes in PDAC cells. It also reduced tumor growth, proliferation, and increased apoptosis in xenograft and PDAC organoid models. Finally, MXRA5, EDIL3, COL13A1, and SLC16A2 were identified as top downstream response genes upon RK-33 treatment and potential new targets to mitigate extracellular matrix remodeling, angiogenesis, cell migration, and cell cycle progression, thereby enhancing the therapeutic efficacy of GEM and 5FU Overall, our data indicate that RK-33 enhances the therapeutic efficacy of GEM and 5FU in mitigating PDAC aggressiveness. Consequently, these findings open new avenues for developing efficacious therapeutic adjuvants to treat advanced pancreatic cancer.
{"title":"Targeting the DDX3/PAF1 axis enhances chemotherapy efficacy in pancreatic ductal adenocarcinoma","authors":"Palanisamy Nallasamy , Parthasarathy Seshacharyulu , Sanchita Rauth , Ashu Shah , Saravanakumar Marimuthu , Venkatesh Varadharaj , Madhulatha Bommideni , Kavita Mallya , Zahraa Wajih Alsafwani , Subodh M. Lele , Venu Raman , Surinder K. Batra , Moorthy P. Ponnusamy","doi":"10.1016/j.canlet.2026.218276","DOIUrl":"10.1016/j.canlet.2026.218276","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that has a poor survival rate of ∼13 % with limited options for effective therapies. DDX3 is a member of the DEAD-box RNA helicase enzyme family. It acts as an adapter protein that interacts with several transcription factors, enhancing their binding ability to the promoters of genes involved in cancer progression. Previously, we demonstrated that PAF1, a component of the RNA polymerase II-associated factor 1 complex, interacts with DDX3 to promote PDAC stemness. Here, we investigated the therapeutic efficacy of RK-33, a small-molecule inhibitor targeting DDX3, in combination with gemcitabine (GEM) and 5-fluorouracil (5FU), which enhanced therapeutic efficacy in KRAS-driven PDAC.-DDX3 and PAF1 exhibit progressively increased expression in various stages and correlate well with poor survival of PDAC. Targeting DDX3/PAF1 significantly mitigated clonogenic, EMT, and stemness phenotypes in PDAC cells. It also reduced tumor growth, proliferation, and increased apoptosis in xenograft and PDAC organoid models. Finally, MXRA5, EDIL3, COL13A1, and SLC16A2 were identified as top downstream response genes upon RK-33 treatment and potential new targets to mitigate extracellular matrix remodeling, angiogenesis, cell migration, and cell cycle progression, thereby enhancing the therapeutic efficacy of GEM and 5FU Overall, our data indicate that RK-33 enhances the therapeutic efficacy of GEM and 5FU in mitigating PDAC aggressiveness. Consequently, these findings open new avenues for developing efficacious therapeutic adjuvants to treat advanced pancreatic cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218276"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046135","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}
Due to its widespread resistance to conventional therapy, Pancreatic Ductal Adenocarcinoma (PDAC) is expected to be the second most common cause of cancer-related death in the United States by 2030. One of the major impediments to therapeutic failure in PDAC is the presence of an immunosuppressive tumor microenvironment (TME). Here, we report the effect of MAP4K4 in regulating innate and adaptive immunity in PDAC-TME in KPC tumors. The IHC analyses revealed that the overexpression of MAP4K4 enhances tumor infiltration of macrophages and neutrophils, while decreasing the number of T cells in KPC PDAC tumors. Furthermore, treating KPC mice with the MAP4K4 pharmacological inhibitor GNE-495 decreased the number of tumor-infiltrating macrophages and neutrophils and increased T cell counts. The RT2 PCR array analysis revealed that treatment with GNE-495 decreased the expression of the co-stimulatory receptor 4-1BB gene in both peripheral and tumor-infiltrating T cells. The combined therapy of GNE-495 and a 4-1BB agonistic monoclonal antibody (mAb) demonstrated the presence of maximal cytotoxic T cells and tumor regression, associated with increased survival in KPC mice. Our study suggests that MAP4K4 regulates innate and adaptive immune cells in pancreatic TME, and pharmacological inhibition of MAP4K4 decreases tumor macrophage and neutrophil counts. Moreover, the rationalized approach of combining a MAP4K4 inhibitor and a 4-1BB agonist mAb induces a T cell-mediated antitumor response, and this combination could serve as a viable treatment for PDAC.
{"title":"MAP4K4 regulates the immune landscape of pancreatic tumor microenvironment and provides an opportunity for immunotherapy","authors":"Sunil Kumar Singh , Sandeep Kumar , Saket Jha , Navin Viswakarma , Harsh Vyas , Piush Srivastava , Rakesh Sathish Nair , Sowdhamini Mahendiran , Niraj Nag , Periannan Sethupathi , Basabi Rana , Jose Trevino , Ajay Rana","doi":"10.1016/j.canlet.2026.218336","DOIUrl":"10.1016/j.canlet.2026.218336","url":null,"abstract":"<div><div>Due to its widespread resistance to conventional therapy, Pancreatic Ductal Adenocarcinoma (PDAC) is expected to be the second most common cause of cancer-related death in the United States by 2030. One of the major impediments to therapeutic failure in PDAC is the presence of an immunosuppressive tumor microenvironment (TME). Here, we report the effect of MAP4K4 in regulating innate and adaptive immunity in PDAC-TME in KPC tumors. The IHC analyses revealed that the overexpression of MAP4K4 enhances tumor infiltration of macrophages and neutrophils, while decreasing the number of T cells in KPC PDAC tumors. Furthermore, treating KPC mice with the MAP4K4 pharmacological inhibitor GNE-495 decreased the number of tumor-infiltrating macrophages and neutrophils and increased T cell counts. The RT<sup>2</sup> PCR array analysis revealed that treatment with GNE-495 decreased the expression of the co-stimulatory receptor 4-1BB gene in both peripheral and tumor-infiltrating T cells. The combined therapy of GNE-495 and a 4-1BB agonistic monoclonal antibody (mAb) demonstrated the presence of maximal cytotoxic T cells and tumor regression, associated with increased survival in KPC mice. Our study suggests that MAP4K4 regulates innate and adaptive immune cells in pancreatic TME, and pharmacological inhibition of MAP4K4 decreases tumor macrophage and neutrophil counts. Moreover, the rationalized approach of combining a MAP4K4 inhibitor and a 4-1BB agonist mAb induces a T cell-mediated antitumor response, and this combination could serve as a viable treatment for PDAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218336"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218807","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 : 2026-04-28Epub Date: 2026-02-16DOI: 10.1016/j.canlet.2026.218328
Zewei Zhao , Wenbin Jia , Zekun Li , Shangheng Shi , Jiaqi Zhou , Chunlan Ning , Zhihao Yu , Xiaofeng Liu , Xuchen Cao , Hong Zheng , Xin Wang , Xiuchao Wang , Yue Yu
Metabolic-epigenetic crosstalk accelerates breast cancer (BC) progression; however, the conduit linking glycolytic flux to chromatin remodeling remains incompletely defined. Here, we delineate a kinase-metabolism-epigenetic axis centered on the Mitogen-Activated Protein Kinase Associated Protein 1 (MAPKAP1, also known as SIN1). Single-cell transcriptomic profiling of highly invasive tumors identifies SIN1 as a central node co-enriched with epithelial-mesenchymal transition and proliferation programs. Biochemical mapping and mass spectrometry demonstrate that SIN1 scaffolds TTK to promote phosphorylation of lactate dehydrogenase A (LDHA) at Tyr239 (p-LDHA^239), thereby amplifying glycolysis and lactate production. The resulting lactate accumulation increases histone H3K18 lactylation (H3K18la), which, as shown by ChIP-seq, is enriched at the Solute Carrier Family 2 Member 3 (SLC2A3, also known as GLUT3) promoter, upregulating GLUT3 and enhancing glucose uptake, thus establishing a self-reinforcing SIN1/TTK/LDHA-H3K18la-GLUT3 feed-forward loop. Structure-function analyses using domain truncations, molecular docking, and high-throughput virtual screening nominate LR-90 as a small-molecule inhibitor of the SIN1/TTK/LDHA complex. LR-90 reduces p-LDHA^239, lactate levels, H3K18la occupancy at the GLUT3 promoter, glucose uptake, invasion, and tumor growth, and it synergizes with standard chemotherapy in patient-derived organoids and mouse xenografts. Clinically, elevated SIN1 expression is associated with adverse pathological features and inferior overall survival. Collectively, these findings link SIN1-mediated recruitment of TTK for LDHA phosphorylation to histone lactylation and GLUT3-driven metabolic reprogramming, and suggest that pharmacological disruption of this axis with LR-90, alone or in combination with standard chemotherapy, may offer a therapeutic strategy for high-glycolytic, high-lactate breast cancer.
{"title":"Targeting the SIN1 mediated TTK/LDHA-H3K18la-GLUT3 axis disrupts metabolic-epigenetic crosstalk and suppresses progression in hyperglycolytic breast cancer","authors":"Zewei Zhao , Wenbin Jia , Zekun Li , Shangheng Shi , Jiaqi Zhou , Chunlan Ning , Zhihao Yu , Xiaofeng Liu , Xuchen Cao , Hong Zheng , Xin Wang , Xiuchao Wang , Yue Yu","doi":"10.1016/j.canlet.2026.218328","DOIUrl":"10.1016/j.canlet.2026.218328","url":null,"abstract":"<div><div>Metabolic-epigenetic crosstalk accelerates breast cancer (BC) progression; however, the conduit linking glycolytic flux to chromatin remodeling remains incompletely defined. Here, we delineate a kinase-metabolism-epigenetic axis centered on the Mitogen-Activated Protein Kinase Associated Protein 1 (MAPKAP1, also known as SIN1). Single-cell transcriptomic profiling of highly invasive tumors identifies SIN1 as a central node co-enriched with epithelial-mesenchymal transition and proliferation programs. Biochemical mapping and mass spectrometry demonstrate that SIN1 scaffolds TTK to promote phosphorylation of lactate dehydrogenase A (LDHA) at Tyr239 (p-LDHA^239), thereby amplifying glycolysis and lactate production. The resulting lactate accumulation increases histone H3K18 lactylation (H3K18la), which, as shown by ChIP-seq, is enriched at the Solute Carrier Family 2 Member 3 (SLC2A3, also known as GLUT3) promoter, upregulating GLUT3 and enhancing glucose uptake, thus establishing a self-reinforcing SIN1/TTK/LDHA-H3K18la-GLUT3 feed-forward loop. Structure-function analyses using domain truncations, molecular docking, and high-throughput virtual screening nominate LR-90 as a small-molecule inhibitor of the SIN1/TTK/LDHA complex. LR-90 reduces p-LDHA^239, lactate levels, H3K18la occupancy at the GLUT3 promoter, glucose uptake, invasion, and tumor growth, and it synergizes with standard chemotherapy in patient-derived organoids and mouse xenografts. Clinically, elevated SIN1 expression is associated with adverse pathological features and inferior overall survival. Collectively, these findings link SIN1-mediated recruitment of TTK for LDHA phosphorylation to histone lactylation and GLUT3-driven metabolic reprogramming, and suggest that pharmacological disruption of this axis with LR-90, alone or in combination with standard chemotherapy, may offer a therapeutic strategy for high-glycolytic, high-lactate breast cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218328"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218850","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 : 2026-04-28Epub Date: 2026-02-18DOI: 10.1016/j.canlet.2026.218329
Ming-Hao Lin , Yuan-Yuan Zhang , Mei-Ju Deng , Zheng-Li Xu , Xing-Xing Yu , Yu Wang , Lan-Ping Xu , Xiao-Hui Zhang , Xiao-Jun Huang , Xiang-Yu Zhao
The leader peptide encoded by exon 1 of the HLA-B gene exhibits a dimorphism at position −21. To investigate the influence of HLA-B leader matching status between recipients and donors on the prognosis of patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as well as potential relevant biological correlates, we conducted a study involving two patient cohorts. Cohort 1 included 1245 patients with hematological malignancies who had complete survival outcome data, while cohort 2 comprised 130 patients who underwent natural killer (NK) cell reconstitution tests post-transplantation. In cohort 1, no significant effect of HLA-B leader matching status on prognosis was found. However, multivariate analysis of a subgroup of patients with myeloid malignancies revealed that HLA-B leader mismatched was associated with significantly higher non-relapse mortality (hazard ratio [HR] = 1.73; P = 0.044), reduced overall survival (HR = 1.67; P = 0.007), and decreased disease-free survival (HR = 1.52; P = 0.015) compared to matched transplants after propensity score matching analysis, findings not observed in lymphoid malignancies. Data from cohort 2 indicated that matched HLA-B leader was associated with favorable NK cell reconstitution in patients with myeloid malignancies. In particular, HLA-B leader matched patients had a higher CD57 expression of total NK and NKG2A+KIR− NK cells, with enhanced NKG2A+KIR− NK cell cytotoxicity (CD107a expression) and IFN-γ secretion at 1, 3, and 6 months post-transplantation (all false discovery rate-adjusted P < 0.05). These findings identify HLA-B leader matching status as a disease-specific prognostic biomarker, suggesting its potential relevance for personalized donor selection considerations in haplo-HSCT settings.
{"title":"Prognostic significance of HLA-B leader matching status and its relationship with NK cell reconstitution in patients with hematological malignancies following haploidentical transplantation","authors":"Ming-Hao Lin , Yuan-Yuan Zhang , Mei-Ju Deng , Zheng-Li Xu , Xing-Xing Yu , Yu Wang , Lan-Ping Xu , Xiao-Hui Zhang , Xiao-Jun Huang , Xiang-Yu Zhao","doi":"10.1016/j.canlet.2026.218329","DOIUrl":"10.1016/j.canlet.2026.218329","url":null,"abstract":"<div><div>The leader peptide encoded by exon 1 of the HLA-B gene exhibits a dimorphism at position −21. To investigate the influence of HLA-B leader matching status between recipients and donors on the prognosis of patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as well as potential relevant biological correlates, we conducted a study involving two patient cohorts. Cohort 1 included 1245 patients with hematological malignancies who had complete survival outcome data, while cohort 2 comprised 130 patients who underwent natural killer (NK) cell reconstitution tests post-transplantation. In cohort 1, no significant effect of HLA-B leader matching status on prognosis was found. However, multivariate analysis of a subgroup of patients with myeloid malignancies revealed that HLA-B leader mismatched was associated with significantly higher non-relapse mortality (hazard ratio [HR] = 1.73; P = 0.044), reduced overall survival (HR = 1.67; P = 0.007), and decreased disease-free survival (HR = 1.52; P = 0.015) compared to matched transplants after propensity score matching analysis, findings not observed in lymphoid malignancies. Data from cohort 2 indicated that matched HLA-B leader was associated with favorable NK cell reconstitution in patients with myeloid malignancies. In particular, HLA-B leader matched patients had a higher CD57 expression of total NK and NKG2A<sup>+</sup>KIR<sup>−</sup> NK cells, with enhanced NKG2A<sup>+</sup>KIR<sup>−</sup> NK cell cytotoxicity (CD107a expression) and IFN-γ secretion at 1, 3, and 6 months post-transplantation (all false discovery rate-adjusted P < 0.05). These findings identify HLA-B leader matching status as a disease-specific prognostic biomarker, suggesting its potential relevance for personalized donor selection considerations in haplo-HSCT settings.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218329"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257662","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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