Cancer Lett
· 2026 Jul · PMID 42061805
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Hypoxia is a hallmark of the tumor microenvironment, but its role in immune evasion in esophageal squamous cell carcinoma (ESCC) remains to be fully elucidated. Here, we demonstrate hypoxia inversely correlated with anti...Hypoxia is a hallmark of the tumor microenvironment, but its role in immune evasion in esophageal squamous cell carcinoma (ESCC) remains to be fully elucidated. Here, we demonstrate hypoxia inversely correlated with anti-tumor immune signatures and CD8 T cell infiltration in clinical samples and murine models. Functionally, reducing hypoxia with the agents TH-302 or PX-478 in the AKR model enhanced intratumoral CD8 T cell infiltration and increased their expression of Granzyme B, IFNγ, and TNFα. Mechanistically, hypoxia-induced immune suppression was dependent on protein lactylation. Inhibiting lactylation reversed the hypoxic suppression of CD8 T cell function and abrogated the hypoxia-driven transcriptional program, which involved pathways like glycolysis, TGFβ, and Notch signaling. This lactylation-dependent regulation operated by facilitating the formation of the HIF-1 transcription complex. Specifically, mass spectrometry identified lactylation at the K172 site of HIF-1α, which was crucial for its binding to HIF-1β and subsequent target gene activation. Furthermore, in a preclinical ESCC model, pharmacological inhibition of HIF-1α with PX-478 synergized with anti-PD-1 therapy, leading to superior tumor control and enhanced CD8 T cell cytotoxicity. Our study identifies HIF-1α K172 lactylation as a pivotal mechanism of hypoxia-mediated immune escape in ESCC, suggesting a therapeutic strategy to improve immunotherapy.
Yang J, You J, Li T
… +14 more, Zhang Z, Zeng W, Wang Q, Chen C, Li Y, Li C, Yi Z, Huang L, Liang R, Wang H, Huang H, Ding D, Lu L, Wei B
Cancer Lett
· 2026 Jul · PMID 42061804
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The efficacy of postsurgical immunotherapy for gastric cancer (GC) remains controversial, and the effect of the number of dissected lymph nodes (DLNs) on the efficacy of immunotherapy remains unknown. We retrospectively...The efficacy of postsurgical immunotherapy for gastric cancer (GC) remains controversial, and the effect of the number of dissected lymph nodes (DLNs) on the efficacy of immunotherapy remains unknown. We retrospectively reviewed 451 patients who received adjuvant or palliative therapies (including immunotherapy and chemotherapy) for GC at nationwide centers between 2020 and 2025 to investigate the influence of DLNs on postsurgical immunotherapy. Prognoses were assessed based on DLNs. In the adjuvant immunotherapy cohort (n = 139), the disease-free survival (DFS) was significantly lower in patients with DLNs >36 compared with those with DLNs ≤36 [hazard ratio (HR), 2.62; 95% confidence interval (CI), 1.39-4.95, P = 0.003)]. Moreover, patients with DLNs≤36 who received combined immunotherapy had a better DFS than patients who received only adjuvant chemotherapy (HR, 0.37; 95% CI, 0.17-0.78, P = 0.006). In the palliative immunotherapy cohort (n = 47), patients with DLNs>36 had significantly lower progression-free survival (PFS) (HR, 3.57; 95% CI, 1.61-7.94, P = 0.001) and DCR (6.67% vs 65.6%, P < 0.001) than those with DLNs≤36. Additionally, when matching with patients who received palliative immunotherapy without previous gastrectomy (DLNs = 0), the PFS decreased progressively in patients with DLNs = 0, DLNs>0 to ≤36, and DLNs>36 (median PFS, 16 vs. 11 vs. 3 months, P = 0.002). In conclusion, excessive lymph node dissection (DLNs≥36) compromised the efficacy of postsurgical adjuvant or palliative immunotherapy for GC.
Xu X, Li Z, Luo J
… +8 more, Chen Y, Song Y, Wu B, Fu Y, Chen J, Liu Y, Wang G, Huang P
Cancer Lett
· 2026 Sep · PMID 42044865
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The therapeutic efficacy of systemic treatments in cancer therapy is invariably limited by the biophysical barriers, including vascular endothelial barrier, extracellular matrix, and elevated interstitial fluid pressure....The therapeutic efficacy of systemic treatments in cancer therapy is invariably limited by the biophysical barriers, including vascular endothelial barrier, extracellular matrix, and elevated interstitial fluid pressure. Ultrasonic cavitation, as a non-invasive modality, can induce a series of biological effects that leverage mechanical forces to breach these biophysical barriers and remodel the tumor microenvironment. This review traces the paradigm shift from thermal coagulation to mechanochemical modulation, where acoustic forces are transduced into profound biological responses via mechanosensitive ion channels and immunogenic signaling pathways. We summarize recent advances in the intelligent engineering of ultrasound-active materials, from vascular-targeted microbubbles and phase-change nanodroplets to oxygen-independent piezocatalysts. Meanwhile, we clinically evaluate the utility of cavitation in enhancing drug delivery and remodeling immune environment, and highlight the milestone approval of histotripsy for non-thermal ablation. Finally, we discuss critical challenges regarding stochasticity and biosafety, proposing a roadmap toward artificial intelligence-guided, closed-loop dosimetry. We predict that by integrating physical mechanics with biological engineering, ultrasonic cavitation may alleviate multidrug resistance and immunosuppression in cancer therapy.
Zhang D, Zhou L, Dai C
… +6 more, Peng J, Tang D, Xu P, Li Q, Xia Q, Qian X
Cancer Lett
· 2026 Jul · PMID 42036013
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Lung cancer is strongly associated with increased extracellular matrix (ECM) stiffness, which correlates with poor patient prognosis. Our study reveals that high-stiffness tumor niches exhibit significant upregulation of...Lung cancer is strongly associated with increased extracellular matrix (ECM) stiffness, which correlates with poor patient prognosis. Our study reveals that high-stiffness tumor niches exhibit significant upregulation of neutrophil extracellular traps (NETs), which enhance the Warburg effect and promote tumor cell proliferation. Using atomic force microscopy (AFM) and multi-immunofluorescence staining (mIF), we demonstrated a spatial correlation between NETs formation and localized ECM stiffness in lung cancer tissues. In Kras/Trp53 transgenic mouse model, bleomycin-induced lung stiffening further increased NETs generation, while genetic ablation of Pad4 (Pad4 mouse model) or pharmacological inhibition of NETs (via LOX mAb, BAPN, or DNase I) reduced tumor burden. Mechanistically, stiffness-driven NETs upregulated glycolytic enzymes and extracellular acidification rate (ECAR) through aberrant mTOR pathway activation. Ex vivo and patient-derived xenograft (PDX) models validated the therapeutic potential of targeting LOX could extracellularly attenuate stiffness of ECM and intracellularly inhibit mTOR pathway. Our findings propose a novel strategy to improve lung cancer outcomes by disrupting the stiffness-NETs-mTOR axis, offering a one target-dual function approach for tumors with stiffening ECM.
Zhu W, Ma C, Zhao X
… +8 more, Song Y, Li J, Feng Y, Sun F, Li Z, Du Y, Kong X, Kong F
Cancer Lett
· 2026 Jul · PMID 42036012
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Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy with limited prognostic biomarkers and therapeutic targets. Lactate-driven lactylation has recently emerged as an important regulator of cancer progression,...Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy with limited prognostic biomarkers and therapeutic targets. Lactate-driven lactylation has recently emerged as an important regulator of cancer progression, but its role in PAAD remains unclear. In this study, integrative analysis of TCGA and GEO datasets, combined with experimental validation, identified a five-gene lactylation-associated signature (LRP3, TTLL6, TSGA13, PRKCG, and SDK2) that effectively stratified PAAD patients by survival risk. High-risk tumors displayed an immunosuppressive phenotype with reduced immune infiltration, Th2-skewed remodeling, checkpoint activation, and distinct mutational and drug-sensitivity features. Among the signature genes, PRKCG was significantly downregulated in PAAD and associated with advanced disease and worse prognosis. PRKCG overexpression inhibited tumor cell proliferation, migration, invasion, and xenograft growth, while enhancing apoptosis. Mechanistically, lactate-induced lactylation impaired PRKCG-dependent activation of the p53 pathway without altering PRKCG expression, and mutation of predicted lactylation sites partially rescued this effect. These findings define a lactylation-associated prognostic model for PAAD and highlight the lactate-PRKCG-p53 axis as a potential therapeutic vulnerability.
Quan M, Liu YK, Zhao Y
… +6 more, Kay M, Sun K, Gavin TP, Pollock RE, Tao WA, Kuang S
Cancer Lett
· 2026 Jul · PMID 42036011
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Notch signaling is an emerging regulator of liposarcoma (LPS), but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alt...Notch signaling is an emerging regulator of liposarcoma (LPS), but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alters the proteomes of LPS-derived extracellular vesicles (EVs). We used quantitative mass spectrometry to profile the EV proteome in multiple contexts: cultured LPS cells, LPS tumor, circulating EVs of LPS-bearing mice, and human LPS samples. We found that Notch signaling increases the secretion of EV proteins that favor tumor progression and metastasis but suppresses immune responses in murine LPS cells. Overlapping murine and human LPS data identifies 18 proteins that are increased in LPS EVs of both species, including endotrophin as a biomarker of LPS. Functional analysis supports a role of LPS EVs in regulating gene expression and behaviors of endothelial cells in TME. Together, these data demonstrate that in addition to its known function in driving tumorigenesis, Notch signaling also regulates TME through EV secretion.
Ali A, Di Pastena F, Biziotis OD
… +9 more, Wang S, Tsakiridis EE, Del Rosso D, Fredenburgh JC, Weitz JI, Hotte SJ, Bramson JL, Steinberg GR, Tsakiridis T
Cancer Lett
· 2026 Aug · PMID 42036010
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Androgen receptor (AR) pathway inhibitors (ARPIs) improve outcomes in advanced prostate cancer (PC) in combination with androgen deprivation therapy (ADT). However, PC rapidly develops ARPI resistance, frequently through...Androgen receptor (AR) pathway inhibitors (ARPIs) improve outcomes in advanced prostate cancer (PC) in combination with androgen deprivation therapy (ADT). However, PC rapidly develops ARPI resistance, frequently through expression of truncated AR variants (AR-Vs), like AR-V7, highlighting a need for more effective therapies. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin, an approved diabetes drug, also suppresses PC growth and inhibits AR-related gene expression. Therefore, we hypothesized that canagliflozin may directly inhibit AR. Cellular and tumor models of PC were subjected to proliferation, clonogenic, and xenograft studies. RNA-seq and siRNA knockdown approaches defined molecular mechanisms. Molecular docking, thermal shift, and surface plasmon resonance assays assessed drug-target interactions. Stable sh-AR full-length (sh-AR-FL) and sh-AR-V7 cell lines were generated to interrogate the transcriptomic impact of AR and prognostic analysis was performed using clinical datasets. We found that canagliflozin suppresses PC growth through AR. It interacts with the AR ligand binding domain (LBD) with estimated affinity comparable to ARPIs and blocks AR signaling. Canagliflozin reduces the transcript and protein levels of the HSP70 chaperone and suppresses the cytoplasmic and nuclear levels of AR-FL and AR-Vs through proteasomal degradation. It mediates substantial reprogramming of PC transcriptional activity, including inhibition of AR pathway, cell-cycle, E2F and MYC hallmark targets. Its gene expression profile overlaps with silencing AR-FL or AR-V7 is associated with improved prognosis in clinical datasets. The results of this study demonstrate the potential for canagliflozin to function as a clinically useful ARPI and support prospective clinical investigation of this drug in PC.
Wang D, Xiao C, Fan T
… +10 more, Deng Z, Yin H, Liu Y, Li J, Ji Y, Cai W, Liao T, Li J, Li C, He J
Cancer Lett
· 2026 Jul · PMID 42031161
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Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality. Although targeted therapies and immunotherapies have improved outcomes, many patients exhibit limited responses due to primary or acquired resistanc...Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality. Although targeted therapies and immunotherapies have improved outcomes, many patients exhibit limited responses due to primary or acquired resistance, underscoring the need to identify novel molecular targets. The Gab family of scaffolding adaptors, including GAB1 and GAB2, are recognized oncogenic regulators, whereas the role of GAB3, implicated in immune cell activation, is poorly defined in solid tumors. Here, we identify GAB3 as a novel tumor suppressor in LUAD. Pan-cancer analysis revealed frequent GAB3 downregulation, and high GAB3 expression was associated with favorable prognosis. Functionally, GAB3 overexpression suppressed LUAD cell proliferation, migration, invasion, and tumor growth in vitro and in vivo. Mechanistically, GAB3 interacted with LYN kinase to inhibit the MAPK signaling pathway and reverse epithelial-mesenchymal transition (EMT). In addition, GAB3 remodeled the tumor immune microenvironment, enhanced CXCL10 secretion, increased CD8 T cell infiltration and effector function, and potently sensitized tumors to anti-PD-1 therapy. Our findings support a dual tumor-suppressive mechanism for GAB3 and propose it as a promising prognostic biomarker and therapeutic target in LUAD.
Basov DD, Dorman MJ, Burton KA
… +3 more, Metropulos AE, Munshi HG, Principe DR
Cancer Lett
· 2026 Jul · PMID 42031160
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Malignant ascites is a devastating complication of several advanced malignancies. Beyond serving as a poor prognostic indicator, the rapid accumulation of ascitic fluid imposes a significant symptom burden that can sever...Malignant ascites is a devastating complication of several advanced malignancies. Beyond serving as a poor prognostic indicator, the rapid accumulation of ascitic fluid imposes a significant symptom burden that can severely worsen quality of life. Although immunotherapy has revolutionized solid tumor oncology, these approaches have shown only limited benefit in the treatment of malignant ascites. Here, we summarize landmark clinical trials exploring immunotherapy as a potential treatment of malignant ascites. We then conceptualize malignant ascites as a functionally distinct immunologic compartment rather than a passive fluid reservoir, highlighting unique immunologic features that may underlie the challenges in translating immunotherapy to this context. By advancing our collective understanding of this unique immune microenvironment, it may become possible to develop rational combination strategies that provide symptomatic relief and meaningfully improve quality of life for patients with end-stage disease.
Li Z, Yang K, Jiang F
… +6 more, Mei J, Zeng T, Zhao X, Liang Y, Huang X, Yin Y
Cancer Lett
· 2026 Aug · PMID 42025744
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Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet their clinical application is constrained by a critical trade-off between potent antitumor efficacy and off-target cardiovascular toxicity. This...Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet their clinical application is constrained by a critical trade-off between potent antitumor efficacy and off-target cardiovascular toxicity. This adverse effect underscores a fundamental biological dilemma: how tumor immunotherapy disrupts cardiovascular homeostasis. Immune cells within the cardiovascular system undergo metabolic adaptations after immune therapy. This intricate crosstalk has brought metabolic checkpoints to the forefront of research. In this review, we systematically outline the features of tumor-associated metabolic remodeling and shared roles in cardiac metabolism and immunometabolism. We elucidate ICIs initiate a cascade of events leading to cardic dysfunction through metabolic signal pathways. Furthermore, we propose that the strategic integration of cutting-edge technologies including spatial metabolomics to enable precise reprogramming of metabolic networks will ultimately decouple the efficacy of cancer immunotherapy from its associated toxicities.
Wang Y, Liu B, Patel H
… +3 more, Yu J, Hu M, Chen ZS
Cancer Lett
· 2026 Jul · PMID 42019605
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Tumor-associated macrophages (TAMs) represent a dominant, plastic component of the tumor microenvironment (TME) that orchestrates immunosuppression, angiogenesis, and therapeutic resistance. Since static biopsies fail to...Tumor-associated macrophages (TAMs) represent a dominant, plastic component of the tumor microenvironment (TME) that orchestrates immunosuppression, angiogenesis, and therapeutic resistance. Since static biopsies fail to capture the spatiotemporal heterogeneity and dynamic phenotypic evolution of TAMs (e.g., M1/M2 polarization), non-invasive imaging is critical. This review systematically critiques the evolution of Positron Emission Tomography (PET) strategies for TAM quantification, classifying innovations into metabolic, functional, and molecular approaches. Moving beyond the limitations of indirect methods-such as [F]FDG and "Trojan horse" nanoparticles constrained by mononuclear phagocyte system (MPS) sequestration-we emphasize the paradigm shift toward high-affinity molecular probes. These target specific biomarkers (e.g., CD206, CD163, CSF1R) and recruitment pathways (e.g., CCR2). We particularly highlight the clinical potential of nanobody- and peptide-based tracers, which demonstrate superior tumor penetration and rapid clearance compared to full-sized antibodies. Concluding with an analysis of translational hurdles, such as interspecies marker discordance, we propose future directions that integrate theranostics, spatial transcriptomics, and AI-driven radiomics. Ultimately, molecular TAM-PET imaging is poised to evolve from an experimental tool into a precision oncology platform for patient stratification and monitoring of immunomodulatory therapies.
Cancer Lett
· 2026 Jul · PMID 42019604
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Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality, arising predominantly in the context of chronic liver injury and cirrhosis. The tumor microenvironment (TME) is a critical orchestrator of HCC...Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality, arising predominantly in the context of chronic liver injury and cirrhosis. The tumor microenvironment (TME) is a critical orchestrator of HCC progression and therapeutic resistance. Neutrophils, the most abundant circulating leukocytes and key first responders in hepatic immunity, play a pivotal and multifaceted role in this process. Under physiological conditions, neutrophils are essential for liver homeostasis and acute injury resolution. However, across the pathological continuum from chronic liver disease to HCC, sustained inflammatory signaling drives a profound reprogramming of neutrophil function. Within the established HCC TME, tumor-associated neutrophils (TANs) are frequently polarized into a protumorigenic phenotype, actively driving disease progression through several core mechanisms: they establish immunosuppressive niches by directly suppressing cytotoxic T-cell function; promote angiogenesis and metastasis via the secretion of factors like VEGF and MMPs; and contribute to genomic instability and therapy resistance through mechanisms such as neutrophil extracellular trap (NET) formation. This functional transition from defenders in acute injury to accomplices in malignant progression underscores the central role of neutrophils in liver pathobiology and HCC pathogenesis. This review synthesizes current knowledge on the recruitment, polarization, and functional diversity of neutrophils in the HCC TME, with a particular focus on their mechanisms in mediating immunosuppression through cellular crosstalk and metabolic reprogramming. We further critically evaluate emerging therapeutic strategies that target neutrophil-centric pathways to resuscitate antitumor immunity, including TAN repolarization, depletion of specific subsets, or functional blockade. Finally, we discuss the translational potential of neutrophil-related biomarkers for patient stratification and the rationale for developing combination therapies. A deeper understanding of the dynamic and pleiotropic roles of neutrophils in HCC is essential for devising more effective immunotherapeutic strategies and improving patient outcomes.
Liu L, Wu Q, Fang S
… +5 more, Hu Z, Yu S, Wang H, Song H, Liu Q
Cancer Lett
· 2026 Jul · PMID 42000030
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Small cell lung cancer (SCLC) harbors pronounced intratumoral heterogeneity, yet epigenetic drivers of subtype plasticity remain poorly understood. Herein, we established paired neuroendocrine (NE)-high and NE-low SCLC o...Small cell lung cancer (SCLC) harbors pronounced intratumoral heterogeneity, yet epigenetic drivers of subtype plasticity remain poorly understood. Herein, we established paired neuroendocrine (NE)-high and NE-low SCLC organoids from pulmonary neuroendocrine cells (PNECs)-specific Trp53/Rb1/Pten-triple knockout mice. NE-high organoids developed prominent axon-like protrusions, while NE-low counterparts exhibited cystic structures. Both subtypes maintained primary tumor genetics and tumorigenicity. Transcriptomics revealed NE-high enrichment of neuronal programs versus innate immune pathway upregulation in NE-low organoids. Mechanistically, Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 enrichment in NE-low organoids suppressed Dnmt3a, causing global DNA hypomethylation that reactivated endogenous retroviruses (ERVs), triggering cytosolic double-stranded RNA (dsRNA) accumulation and consequent antiviral interferon response. Notably, Carm1 stabilized Dnmt3a via transient methylation. Targeting Dnmt3a or Carm1 in NE-high organoids drove their transition to a NE-low state with ERV de-repression. Collectively, these findings establish a PRC2/CARM1/DNMT3A axis orchestrating SCLC plasticity, identifying DNA methyltransferase inhibition as a potential therapeutic strategy targeting SCLC heterogeneity and immunosuppression.
Zou H, Guo Y, Pan Q
… +12 more, Chen Y, Huang J, Zhou Y, Yang X, Zhu Y, Mo L, Cai J, Chen ZS, Liu Y, Xu Y, Zeng L, Pan Y
Cancer Lett
· 2026 Jul · PMID 42000029
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Colorectal cancer (CRC) is among the most prevalent malignancies in humans. Despite significant advances over the past few decades, the underlying mechanisms remain incompletely understood. Tripartite motif (TRIM) family...Colorectal cancer (CRC) is among the most prevalent malignancies in humans. Despite significant advances over the past few decades, the underlying mechanisms remain incompletely understood. Tripartite motif (TRIM) family proteins have been established as critical players in tumorigenesis, primarily through mediating protein degradation via the ubiquitin-proteasome system (UPS). Accumulating evidence suggests that TRIM family members are involved in CRC progression by regulating multiple cellular processes, exhibiting both tumor-suppressive and oncogenic functions depending on the context. Given the pivotal roles of TRIM proteins in cellular homeostasis and the substantial challenges in CRC treatment, a deeper understanding of their specific contributions to this disease is urgently needed. Therefore, this review systematically outlines the distinct biological functions and molecular mechanisms of various TRIM proteins in CRC, including their roles in tumorigenesis and invasiveness, drug sensitivity, the tumor immune microenvironment (TIME), cell cycle regulation, and metabolic reprogramming. A thorough comprehension of the interactions between TRIM proteins and CRC-related signaling pathways is a crucial prerequisite for exploiting TRIMs as novel biomarkers and potential therapeutic targets in CRC.
Yao Z, Wang R, Chen B
… +8 more, Zhao X, Zhang J, Zhou S, Xu A, Wu L, Zhang J, Xu F, Zhao G
Cancer Lett
· 2026 Jul · PMID 41997286
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The replication protein A (RPA) complex safeguards single-stranded DNA (ssDNA) and coordinates repair during replication stress and homologous recombination (HR), but the mechanisms regulating its timely engagement and r...The replication protein A (RPA) complex safeguards single-stranded DNA (ssDNA) and coordinates repair during replication stress and homologous recombination (HR), but the mechanisms regulating its timely engagement and release at damage sites are not well defined. Here, we identified RNF185 as a critical E3 ligase that orchestrates temporally distinct patterns of RPA1 ubiquitination-shifting from K6/K63- to K48-linked chains-to precisely regulate HR and replication fork restart upon DNA damage. Mechanistically, RNF185 undergoes ATM/ATR-dependent phosphorylation at threonine 106 and translocates into the nucleus via interaction with NUP88 following DSBs. In the early response phase, RNF185 promotes K6/K63-linked ubiquitination of RPA1, stabilizing RPA1 on ssDNA to facilitate replication fork restart and efficient recruitment of RPA1 to damage sites. At later stages, RNF185 competes with the deubiquitinase OTUB1 for RPA1 binding and facilitates K48-linked ubiquitination at lysine 458, promoting RPA1 degradation and its removal from chromatin. Loss of RNF185 disrupts RPA1 turnover, impairs HR efficiency, destabilizes replication forks, and sensitizes tumor cells to irradiation and cisplatin. In vivo, RNF185 depletion significantly enhances the therapeutic efficacy of radiotherapy. In summary, this study demonstrates that RNF185 is a key regulatory factor in HR and replication fork restart, aiding cells in their response to radio- or chemotherapy induced DNA damage in clinical settings.
Takao S, Furusawa A, Kano M
… +8 more, Yamamoto H, Kano M, Suzuki M, Fukushima H, Okuyama S, Kitamura K, Choyke PL, Kobayashi H
Cancer Lett
· 2026 Jul · PMID 41997285
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Near-infrared photoimmunotherapy (NIR-PIT) is an innovative cancer treatment that provides both direct and selective killing of cancer cells and enhancement of the host's antitumor immune response. In Japan, EGFR-targete...Near-infrared photoimmunotherapy (NIR-PIT) is an innovative cancer treatment that provides both direct and selective killing of cancer cells and enhancement of the host's antitumor immune response. In Japan, EGFR-targeted NIR-PIT is already used clinically for head and neck cancer; however, there is limited understanding of the immune response kinetics of EGFR-targeted NIR-PIT. This limitation poses a significant barrier to further development of NIR-PIT, such as expanding its applications to other cancers and combination therapies. The purpose of this study is to establish a model incorporating EGFR-targeted NIR-PIT using a new anti-mouse EGFR (mEGFR) antibody and to evaluate its potential in an immunocompetent model. Employing a syngeneic tumor expressing mEGFR, mEGFR-targeted NIR-PIT showed significant tumor suppression in both the LL/2-luc and TS/A models, with the latter also showing improved survival. Analysis of the host immune response after NIR-PIT in the TS/A model indicated a temporary early increase in dendritic cell maturation markers, followed by a rise in intratumoral CD8 T cells from day three after treatment. Combining CTLA-4 blockade therapy with mEGFR-targeted NIR-PIT resulted in strong tumor growth inhibition and prolonged survival in both models. Notably, the group received early CTLA-4 therapy, which aligns with the timing of immune activation after NIR-PIT, demonstrated better antitumor effect than the group receiving late CTLA-4 therapy. In summary, this mEGFR-targeted NIR-PIT model enabled detailed analysis of NIR-PIT-mediated immune effects and facilitated the establishment of the optimal treatment schedule for CTLA-4 blockade. This preclinical NIR-PIT model would provide valuable insights into improving treatment strategies.
Cheng Z, Ding F, Yin J
… +14 more, Wang Y, Gao Y, Ge X, Zhang J, Wang X, Zhao M, Zhao N, Shu C, Wang X, Qian X, Qian C, Ji J, You Y, Shi Z
Cancer Lett
· 2026 Jul · PMID 41997284
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Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and radiotherapy is a key treatment option. However, glioblastoma stem cells (GSCs) can develop resistance to radiotherapy through metabolic reprog...Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and radiotherapy is a key treatment option. However, glioblastoma stem cells (GSCs) can develop resistance to radiotherapy through metabolic reprogramming, which often results in tumor recurrence. Here we found that glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was phosphorylated at threonine 8 (T8) by ataxia telangiectasia mutated (ATM) upon irradiation (IR), leading to enhanced binding of PGK1 to phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for the serine synthesis pathway (SSP). PGK1 subsequently functioned as a protein kinase to phosphorylate PHGDH at T60, which resulted in enhanced PHGDH enzymatic activity and increased serine synthesis to fuel the production of S-adenosylmethionine (SAM). Increased SAM then promoted the levels of histone H3K36 trimethylation (H3K36me3) to recruit RAD51 to engage homologous recombination (HR)-mediated DNA damage repair to confer resistance of GSCs to IR. Importantly, both inhibiting PHGDH T60 phosphorylation and suppressing its enzymatic activity sensitized GSCs to IR, inhibited growth of orthotopich xenografts, and prolonged survival of tumor-bearing mice. Furthermore, clinical analysis indicated that phosphorylation levels at both PHGDH T60 and PGK1 T8 corresponded closely with the poor prognosis of GBM patients. This study revealed an ATM-PGK1-PHGDH signaling axis that promoted serine synthesis to confer resistance of GSCs to IR, and suggested that targeting PHGDH may serve as a potential strategy to overcome radioresistance in GBM.