Wang H, Wang X, Zhang W
… +15 more, Hu S, Chen H, Liu J, Xue H, Yang J, Li Y, Wang D, Li C, Du M, Zheng Z, Zhao J, Maisaidi R, Liu C, Xiang Y, Hong L
Cancer Lett
· 2026 Aug · PMID 42176791
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Acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors limits the durability of niraparib maintenance therapy in epithelial ovarian cancer. Here, integrated multi-omic and functional analyses of paired pare...Acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors limits the durability of niraparib maintenance therapy in epithelial ovarian cancer. Here, integrated multi-omic and functional analyses of paired parental and niraparib-resistant models identified DNMT3B-dependent promoter hypermethylation and silencing of argininosuccinate synthase 1 (ASS1), establishing an arginine-auxotrophic state in resistant cells. Despite impaired de novo arginine synthesis, resistant cells maintained intracellular arginine through enhanced extracellular acquisition. Arginine deprivation alone induced a largely cytostatic state characterized by mitochondrial dysfunction, oxidative stress, and energetic imbalance, whereas its combination with niraparib produced marked synergy, amplifying DNA damage, suppressing homologous recombination, and driving cell death. Mechanistically, arginine restriction depleted NAD(P)H and acetyl-CoA pools, reduced histone H3 acetylation, and compressed chromatin accessibility at DNA repair loci, thereby intensifying niraparib-induced genotoxic stress. Resistant cells also displayed persistent mTORC1 activation and blunted autophagic flux; mTORC1 inhibition restored autophagy and niraparib sensitivity but attenuated the incremental benefit of arginine deprivation, identifying mTORC1-constrained autophagy as a key determinant of this vulnerability. In vivo, a well-tolerated 50% arginine-restricted diet lowered circulating and intratumoral arginine and potentiated niraparib across resistant xenograft, patient-derived, and maintenance-mimicking models. Clinically, DNMT3B-high/ASS1-low tumors were associated with shorter progression-free survival, and serial plasma arginine declined prior to progression during niraparib maintenance, supporting plasma arginine dynamics as an exploratory candidate monitoring biomarker. Together, these findings define an epigenetically fixed arginine dependency in niraparib-resistant ovarian cancer and support partial dietary arginine restriction as a practical resensitization strategy.
Wei W, Zhang Z, Zhao X
… +6 more, Duan J, Ma J, Deng S, Liu Y, Sun L, Wang J
Cancer Lett
· 2026 Aug · PMID 42173274
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Metabolic reprogramming enables tumor cells to evade immune surveillance, yet the mechanisms linking specific metabolic alterations to immune evasion remain incompletely understood. We found that in metabolic dysfunction...Metabolic reprogramming enables tumor cells to evade immune surveillance, yet the mechanisms linking specific metabolic alterations to immune evasion remain incompletely understood. We found that in metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) cells, aberrant accumulation of bile acids impairs the NOD-like receptor family CARD domain containing 5-mediated major histocompatibility complex class I antigen presentation pathway, thereby leading to loss of antigenicity in tumor cells. Bile acid retention in tumor cells results primarily from the downregulation of the efflux pump ABCB11, driven by G protein-coupled receptor 120-mediated FXR suppression under lipid-rich conditions. Furthermore, genetic inactivation of NLRC5 abolishes the recovery of MHC-I expression and antitumor immunity upon bile acid reduction. Treatment with Tropifexor, a potent selective FXR agonist, synergizes with immune checkpoint blockade, significantly reducing tumor burden and potentiating the intratumoral adaptive immune response in mice. Thus, we reveal that intracellular bile acid accumulation suppresses both tumor antigenicity and intrinsic antitumor immunity. This insight provides a therapeutic target for improving immunotherapy outcomes in MASH-HCC.
Xu H, Zhang L, Fu M
… +9 more, Yang H, Wu R, Ma J, You M, Zhang J, Lv K, Wu Y, Ye D, Hua W
Cancer Lett
· 2026 Aug · PMID 42173273
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Isocitrate dehydrogenase-mutant (IDH-MUT) gliomas exhibit distinct metabolic profile marked by 2-hydroxyglutarate (2-HG) accumulation at the expense of α-ketoglutarate. How these tumors maintain the tricarboxylic acid (T...Isocitrate dehydrogenase-mutant (IDH-MUT) gliomas exhibit distinct metabolic profile marked by 2-hydroxyglutarate (2-HG) accumulation at the expense of α-ketoglutarate. How these tumors maintain the tricarboxylic acid (TCA) cycle, however, remained unclear. We conducted comprehensive metabolomic profiling using clinical cohorts, cell lines, and patient-derived organoids (PDOs). The metabolic dynamics of TCA and urea cycles were interrogated using stable isotope tracing with C-aspartate, U5-C-N-aspartate, NHCl and N-glutamate. The functional role of carbamoyl-phosphate synthase 1 (CPS1), the key enzyme of the urea cycle, was validated through inhibition experiments in vitro, in vivo and in PDO model, followed by seahorse respirometry and electron microscopy. Metabolomic profiling of two glioma cohorts consistently showed elevated urea cycle metabolites in IDH-MUT tumors. We identified CPS1 as a metabolic checkpoint sustaining TCA cycle through half urea cycle (from ammonia to arginine). Of note, CPS1 upregulation drove fumarate anaplerosis to sustain TCA flux in IDH-MUT gliomas. Thus, CPS1 inhibition not only reduced fumarate levels but also decreased oncometabolite 2-HG both in vitro and in vivo. Consistently, CPS1 inhibition impaired mitochondrial respiration and suppressed tumor growth in vitro, in vivo and in PDOs. Taken together, metabolic checkpoint CPS1 orchestrates half urea cycle to replenish the TCA cycle in IDH-MUT gliomas. Targeting CPS1 represents a promising metabolic therapeutic target for this glioma subtype.
Huang R, Yang Z, Dong Y
… +7 more, Liang M, Chen T, Xie H, Liu J, Jiang Y, Tian D, Bian E
Cancer Lett
· 2026 Aug · PMID 42167397
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Resistance to temozolomide (TMZ) is a major driver of treatment failure and high mortality in patients with glioblastoma (GBM). However, the mechanisms underlying TMZ resistance, especially intrinsic resistance, remain i...Resistance to temozolomide (TMZ) is a major driver of treatment failure and high mortality in patients with glioblastoma (GBM). However, the mechanisms underlying TMZ resistance, especially intrinsic resistance, remain incompletely elucidated. Through integrative multi-omics analyses, we identified a novel super-enhancer-driven circular RNA, circMLB, which is highly overexpressed in TMZ-R GBM. Both in vitro and in vivo studies robustly demonstrate that circMLB significantly enhances TMZ resistance in GBM. Mechanistically, the transcription factor PAF1 forms a protein complex with BRD4 that is enriched in the super-enhancer region, thereby upregulating circMLB expression. Furthermore, highly expressed circMLB directly binds to PKR, triggering stress granule assembly and ultimately reinforcing TMZ resistance in GBM. Importantly, we identified a novel PKR inhibitor, lurasidone, which synergizes with TMZ to exert potent anti-tumor activity against TMZ-R GBM in preclinical models. Our findings uncover a previously unrecognized SE-circMLB-PKR axis mediating intrinsic TMZ resistance and highlight the lurasidone-TMZ combination as a promising therapeutic strategy to surmount TMZ resistance in GBM.
Chen J, Ding B, Tiantian X
… +9 more, Chaofeng D, Jianhua L, Shanhe H, Chenguang H, Jun M, Yifan J, Xie H, Wu J, Zheng S
Cancer Lett
· 2026 Aug · PMID 42167396
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Lysine acetylation affects hepatocellular carcinoma (HCC) malignancy through multiple pathways. Evidence from our laboratory and other groups indicates that long chain acyl CoA synthetase 4 (ACSL4) is a crucial oncoprote...Lysine acetylation affects hepatocellular carcinoma (HCC) malignancy through multiple pathways. Evidence from our laboratory and other groups indicates that long chain acyl CoA synthetase 4 (ACSL4) is a crucial oncoprotein in HCC. However, the precise mechanisms underlying the post-translational regulation of ACSL4 acetylation remains unknown. Here, we report a previously unknown mechanism of ACSL4 regulation involving acetylation at the lysine 49 (K49) site by the acetyltransferase MOF. ACSL4 acetylation hindered its degradation via the ubiquitin-proteasome pathway. Using mass spectrometry and subsequent verification, we demonstrated that TRIM21 is an E3 ubiquitin ligase responsible for ACSL4 proteasomal degradation. Further mechanistic studies revealed that MOF-mediated ACSL4-K49 acetylation counteracted the TRIM21-mediated degradation of ACSL4. Functionally, we demonstrated that acetylated ACSL4 promotes lipid accumulation and HCC progression, both in vitro and in vivo. Clinically, ACSL4-K49 acetylation is frequently increased in HCC samples, and elevated ACSL4-K49 acetylation is associated with poor prognosis in patients with HCC. Together, these findings unveil a novel regulatory mechanism of ACSL4, highlighting its pivotal role in modulating HCC progression.
Nguyen TN, Nguyen-Tran HH, Huang KH
… +4 more, Kuo KL, Liao SM, Lin WC, Hsu T
Cancer Lett
· 2026 Aug · PMID 42167395
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Clear-cell renal cell carcinoma (ccRCC) is defined by cancer cells with lipid-filled cytoplasm that appears "clear" in tissue preparations; however, the origin of these lipids and their role in tumor progression remain u...Clear-cell renal cell carcinoma (ccRCC) is defined by cancer cells with lipid-filled cytoplasm that appears "clear" in tissue preparations; however, the origin of these lipids and their role in tumor progression remain unclear. Notably, cultured ccRCC cells rarely exhibit the clear-cell phenotype in vitro, suggesting that lipid accumulation in ccRCC is not cell-autonomous. Here we show that tumor-associated macrophages (TAMs) undergo immunometabolic reprogramming and serve as major suppliers of lipids for ccRCC cells. Upon activation by the tumor suppressor gene VHL-deficient kidney tubule cells, TAMs acquire adipogenic and cholesterol metabolic signatures, accumulate lipids, and differentiate into lipid-laden macrophages (LLMs) via a TGF-β-APOE-dependent pathway. LLMs then transfer lipids directly to tumor cells through tunneling nanotubes (TNTs). Lipidomic analyses revealed that LLMs and recipient tumor cells share nearly identical lipid profiles enriched in cholesterol and phosphatidates, but not triglycerides. In patient cohorts, elevated APOE expression levels in macrophages (MΦs) correlated with advanced disease stages. In vivo, disruption of MΦ-specific APOE expression abrogated the clear-cell phenotype, reduced tumor growth, and suppressed metastasis in autochthonous and orthotopic xenograft ccRCC models. These findings identify a previously unrecognized MΦ-tumor crosstalk in which reprogrammed TAMs supply lipids to tumor cells, driving the clear-cell phenotype and disease progression. Targeting the TGF-β-APOE axis or TNT-mediated lipid transfer represents a potential therapeutic strategy. More broadly, this work supports a "metabolic checkpoint" paradigm, revealing a therapeutically amenable vulnerability in ccRCC.
Pan J, Pan S, Lei Y
… +15 more, Li J, Zhong X, Tang L, Xu S, Ling S, Lu D, Wang K, Hao S, Li L, Wu Z, Wang H, Cheng T, Shen J, Xu X, Wei Q
Cancer Lett
· 2026 Sep · PMID 42155697
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Although immunotherapy-based regimens have improved overall survival for some patients with advanced hepatocellular carcinoma (HCC), many patients ultimately experience disease progression. Macrophages are abundant in th...Although immunotherapy-based regimens have improved overall survival for some patients with advanced hepatocellular carcinoma (HCC), many patients ultimately experience disease progression. Macrophages are abundant in the HCC microenvironment and represent promising therapeutic effectors, yet the potential of combining chimeric antigen receptor macrophages (CAR-M) with macrophage checkpoint targeting remains underexplored. Given that glypican-3 (GPC3), a cell-surface heparan sulfate proteoglycan, is highly expressed in HCC, we developed a GPC3-targeted CAR-M system and evaluated its efficacy alone and in combination with USP22 inhibition. USP22, a deubiquitinating enzyme previously linked to tumor CD24 expression, was selected as a combinatorial target to potentially relieve CD24-associated phagocytic suppression. In vitro assays demonstrated that GPC3 CAR-M cells exhibited specific binding, phagocytosis, and potent cytotoxicity against multiple GPC3-positive HCC cell lines. RNA sequencing and flow cytometry revealed a statistically significant positive correlation between USP22 and the macrophage checkpoint CD24. The addition of the USP22 inhibitor significantly enhanced the tumor-killing capacity of CAR-M in a dose-dependent manner and was associated with reduced CD24 expression on tumor cells. This combinatory strategy robustly suppressed tumor growth in both a murine peritoneal dissemination model and a patient-derived xenograft (PDX) model of HCC. Importantly, the enhanced efficacy was consistently observed across CAR-M cells derived from THP-1, human monocyte-derived macrophages (hMDMs), and human pluripotent stem cells (hPSCs), underscoring its broad applicability. Our findings provide proof-of-concept preclinical evidence supporting further evaluation of combining GPC3 CAR-M therapy with USP22 inhibition as a potential immunotherapeutic strategy for HCC.
Wang Y, Zheng J, Zhang K
… +11 more, Mo W, Yang X, Cui P, Liu C, Zheng L, Xia S, Sun M, Wang B, Mei M, Zhou X, Ren Y
Cancer Lett
· 2026 Aug · PMID 42144099
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A high rate of metastasis remains a challenge for the treatment of adenoid cystic carcinoma (ACC), yet the underlying mechanism of lung metastasis remains elusive. By integrating single-cell RNA sequencing and bulk trans...A high rate of metastasis remains a challenge for the treatment of adenoid cystic carcinoma (ACC), yet the underlying mechanism of lung metastasis remains elusive. By integrating single-cell RNA sequencing and bulk transcriptomics with multiplex immunohistochemistry, we identified a metastatic niche consisting of IL1B tumor-associated macrophages (TAMs), CD24 luminal-like tumor cells, ACKR1 endothelial cells (ECs) and HSPA1ACD8 T cells. Importantly, we revealed that IL1B TAMs play diverse roles in the processes of tumor cell intravasation and colonization, two fundamental steps supporting metastatic outgrowth. In primary lesions, IL1B TAMs release elevated levels of VEGFA and MMPs, thereby coupling sprouting angiogenesis with extracellular matrix remodeling to facilitate cancer cell intravasation. In metastatic lesions, IL1B TAMs bind to IL-1R1 on ACKR1 ECs to upregulate the expression of the adhesion molecule SELP, which can attract CD24 luminal-like tumor cells for lung colonization. IL1B TAMs also increase the stress response state of HSPA1ACD8 T-cell recruitment and induce T-cell exhaustion, thereby facilitating the survival of disseminated tumor cells. Mechanistically, MIF derived from CD24 tumor cells increases the transcription of IL1B in TAMs. We also reported that the infiltration of IL1B TAMs increased steadily with increasing lung metastatic progression in mice bearing metastatic ACC cells. Elevated plasma IL-1β and VEGFA levels are associated with increased metastatic burden and poor overall survival in patients with ACC. Our findings reveal the critical role of IL1B TAMs in reshaping the metastatic tumor immune microenvironment and reveal a potential therapeutic vulnerability for metastatic ACC.
Zhang Q, Cao Z, Yan S
… +4 more, Chen B, Huang B, Liu Z, Zhao Y
Cancer Lett
· 2026 Aug · PMID 42144098
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Pancreatic ductal adenocarcinoma is characterized by a fibrotic and metabolically active tumor microenvironment where cancer-associated fibroblasts (CAFs) mediate metabolic crosstalk, extracellular matrix (ECM) remodelin...Pancreatic ductal adenocarcinoma is characterized by a fibrotic and metabolically active tumor microenvironment where cancer-associated fibroblasts (CAFs) mediate metabolic crosstalk, extracellular matrix (ECM) remodeling, and immune regulation. However, the metabolic and spatial heterogeneity of CAFs remains incompletely understood. We integrated spatial transcriptomics and spatial metabolomics data from PDAC tissues and performed SpatialGlue-based multimodal clustering to define CAF subtypes. To characterize metabolic communication, we developed an optimal transport (OT)-based metabolic inference framework to quantitatively model metabolite association between CAFs and tumor cells. Subtype-specific features were independently validated using an independent spatial metabolomics cohort and multiplex immunofluorescence (mIHC) staining. Furthermore, these features were correlated with clinical outcomes via TCGA-PAAD deconvolution. Spatial multi-omics integration identified three robust CAF subtypes with distinct signatures. OT analysis revealed differential metabolic interactions: CAF_C0 mediated amino acid/peptide transfer, CAF_C1 was the primary source of lipids, while CAF_C2 exhibited limited metabolic association but stronger immune and ECM signaling activity. Deconvolution confirmed that CAF composition was strongly associated with prognosis; CAF_C2 enrichment predicted poorer survival and gemcitabine resistance, whereas a higher CAF_C0/CAF_C1 balance correlated with improved outcomes. By combining spatial multi-omics with OT-based modeling, this study delineates metabolically and spatially distinct CAF states with clinical relevance. Our findings suggest CAFs act as both metabolic donors and immune-ECM regulators, providing new insights into stromal reprogramming and potential subtype-specific therapeutic targets in PDAC.
Tang Z, Li T, Yang Z
… +10 more, Zhang Y, Zhou Y, Deng X, Chen W, Huang D, Zhu L, Yan X, Shao H, Luo Z, Luo L
Cancer Lett
· 2026 Aug · PMID 42144097
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Phosphatidylethanolamine binding protein 4 (PEBP4) is a multifunctional protein. The role of intracellular PEBP4 in cancer is well established. However, as a secreted protein, its extracellular functions have yet to be e...Phosphatidylethanolamine binding protein 4 (PEBP4) is a multifunctional protein. The role of intracellular PEBP4 in cancer is well established. However, as a secreted protein, its extracellular functions have yet to be elucidated. Thus, the present study attempted to decipher the functions of the secreted PEBP4. Here, we demonstrated that PEBP4 was upregulated in colorectal cancer (CRC) specimens and was also elevated in the serum of CRC patients. Our results revealed that the secreted PEBP4 (sPEBP4) stimulated the proliferation and migration of colon cancer cells, an event that was prevented by treatment with antibodies against PEBP4 or by mutating the N-glycosylation site (N169 to Q). Our studies indicated that the action of sPEBP4 was different from that of its cellular counterpart. Further, co-injection of the sPEBP4 with colon cancer cells promoted tumorigenesis and lung metastasis in vivo. Mechanistically, sPEBP4 increased phosphorylation of Smad2/3 and Akt/mTOR, which was blocked by the TGFβRⅠ inhibitor SB525334, siRNA or a dominant-negative mutant of TGFβRI, but not by knockdown of IGF-1R or EGFR. In vitro surface plasmon resonance assay revealed that sPEBP4 directly associated with TGFβRs. Finally, sPEBP4 enhanced the stability of TGFβRI by upregulating USP4 through a mechanism similar to TGF-β. Collectively, our study for the first time demonstrates that sPEBP4 activates the TGF-β signaling pathway to promote CRC progression in a TGFβ-independent manner. This would prompt further studies to explore if sPEBP4 could serve as a potential candidate for colorectal cancer therapy or a biomarker for diagnosis, prognosis, and therapeutic responses.
Zhang L, Yu X, Gong C
… +8 more, Han L, Li C, Zhang X, Han P, Yang Y, Huo Y, Zhang N, Yang M
Cancer Lett
· 2026 Aug · PMID 42142704
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It remains unclear whether super-enhancers (SEs) can drive expression of circular RNAs (circRNA) in gastrointestinal cancers (GI cancers). We first identified circRREB1 as a novel SE-driven circRNA in GI cancers and HNRN...It remains unclear whether super-enhancers (SEs) can drive expression of circular RNAs (circRNA) in gastrointestinal cancers (GI cancers). We first identified circRREB1 as a novel SE-driven circRNA in GI cancers and HNRNPL as the RNA binding protein controlling circRREB1 biogenesis. Indeed, SE-driven HNRNPL leads to high circRREB1 expression in GI cancers, which is regulated by transcription factor MAZ. circRREB1 could promote invasion and metastasis of cancer cells in vitro and in vivo. Mechanistically, circRREB1 binds to the SRSF3-XRN1-YTHDC2 complex in cytoplasm, destabilizes the mA-modified CD44 mRNAs, and, thus, enhances metastasis of cancer cells. Consistently, high circRREB1 levels in malignant tissues are associated with poor patient prognosis. Although showing no impacts on tumor growth in nude mice, circRreb1 accelerates tumor proliferation in immunocompetent mice. Interestingly, circRreb1 elevates Ets1 expression through a competing endogenous RNA mechanism, up-regulates Cxcl2 expression and secretion, drives myeloid-derived suppressor cells (MDSCs) infiltration to tumors and contributes to formation of immunosuppressive tumor microenvironments. In line with this, depletion of MDSCs abrogates the oncogenic effects of circRreb1 in vivo. Notably, circRREB1 silencing synergizes with anti-PD1 therapy to activate antitumor immunity, offering novel insights into circRNA-mediated cancer epigenetics and promising therapeutic targets.
Li KC, Gan S, Lu S
… +7 more, Yuan TK, Dong ZN, Gao C, Chen SW, Zhang LX, Wang DG, Wu YB
Cancer Lett
· 2026 Aug · PMID 42142703
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Osimertinib resistance remains a major obstacle to durable disease control of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), yet the regulatory circuitry that sustains a stem-like drug...Osimertinib resistance remains a major obstacle to durable disease control of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), yet the regulatory circuitry that sustains a stem-like drug-tolerant state is incompletely understood. Here, the deubiquitinase (DUB) USP48 was identified as a critical determinant of acquired resistance through stabilization of Y-box binding protein 1 (YBX1) and reinforcement of Wnt/β-catenin signaling. CRISPR-Cas9 dropout screening of patient-derived organoids under osimertinib selection, integrated with multi-omics profiling and clinical correlation analyses, identified USP48 as a functionally selected vulnerability factor in resistant NSCLC. Mechanistically, USP48 associated with YBX1 and removed K48-linked polyubiquitin chains to prevent proteasomal degradation, thereby enabling YBX1-dependent transcriptional activation of PTK7 and subsequent amplification of Wnt-driven stemness programs. Notably, the canonical Wnt effector TCF7L2 directly upregulated USP48 transcription, establishing a positive feedback loop that locked resistant cells in a stable stem-like state. Therapeutically, genetic or pharmacological disruption of this axis, including inhibition of USP48 activity, blockade of downstream Wnt transcriptional output, disruption of the USP48-YBX1 interaction with glycyrrhizic acid, and lipid nanoparticle-mediated delivery of siUSP48-restored osimertinib sensitivity, achieved robust antitumor efficacy with survival benefits in orthotopic and patient-derived xenograft models. Collectively, our findings defined a DUB-centered positive feedback circuit that sustained osimertinib resistance, and highlighted USP48 as a therapeutically useful node to overcome EGFR-TKI resistance of EGFR-mutant NSCLC.
Sabit H, Ghazy A, Albogami KFKM
… +3 more, Abdelhadi OE, Abdel-Ghany S, Arneth B
Cancer Lett
· 2026 Aug · PMID 42142702
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Circadian rhythms orchestrate physiological processes through molecular clocks, regulating up to 43% of genes and influencing breast cancer progression. This review synthesizes recent evidence linking circadian disruptio...Circadian rhythms orchestrate physiological processes through molecular clocks, regulating up to 43% of genes and influencing breast cancer progression. This review synthesizes recent evidence linking circadian disruption-from shift work, light-at-night exposure, and social jetlag-to increased breast cancer risk and metastasis. Epidemiological studies, including large cohorts like the Nurses' Health Study III, show a 78% higher risk with long-term night shifts, mediated by hormonal disruptions and accelerated cellular aging. Molecular mechanisms reveal subtype-specific clock gene alterations: luminal tumors exhibit estrogen-driven dysrhythmia, HER2-positive tumors show signaling pathway disruptions, and triple-negative tumors feature epigenetic silencing. EMT, invasion, and niche preparation display temporal regulation, with chronodisruption promoting protumorigenic environments. Clinical evidence supports chronotherapy, timing treatments like chemotherapy and immunotherapy to circadian phases for enhanced efficacy and reduced toxicity. Biomarkers from wearables enable personalized interventions, addressing health disparities in shift workers. Integrating circadian biology into oncology promises transformative precision medicine, with ongoing trials validating chronotherapeutic protocols.
Dang F, Na J, Xiao L
… +4 more, Tian X, Shao J, Zhong L, Zhao Y
Cancer Lett
· 2026 Aug · PMID 42142701
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Drug resistance remains a principal barrier to effective cancer therapy, with the tumor microenvironment (TME) serving as a central modulator. Among TME components, cancer-associated fibroblasts (CAFs) are the most abund...Drug resistance remains a principal barrier to effective cancer therapy, with the tumor microenvironment (TME) serving as a central modulator. Among TME components, cancer-associated fibroblasts (CAFs) are the most abundant stromal cells and pivotal orchestrators of tumor initiation, progression, and therapeutic resistance. CAFs promote drug resistance through diverse mechanisms, including secretion of cytokines and chemokines, extracellular matrix remodeling, and direct tumor cell interactions. Accumulating evidence further reveals their multifaceted role in resistance via TME remodeling and dynamic crosstalk with immune and endothelial cells. This review provides a comprehensive synthesis of CAF-mediated drug resistance across multiple malignancies-breast, pancreatic, lung, ovarian, prostate, gastric, and hepatobiliary cancers-and examines how CAFs modulate tumor cell behavior, drug metabolism, efflux pathways, and the broader TME. Emerging CAF-targeted strategies and future therapeutic directions are also discussed, highlighting opportunities to overcome drug resistance and improve clinical outcomes.
Cancer Lett
· 2026 May · PMID 42140345
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Crotonylation is a lysine acylation modification that links cellular metabolism to epigenetic regulation. Its rigid planar crotonyl group is specifically recognized by "readers" such as YEATS/DPF and confers strong confo...Crotonylation is a lysine acylation modification that links cellular metabolism to epigenetic regulation. Its rigid planar crotonyl group is specifically recognized by "readers" such as YEATS/DPF and confers strong conformational regulatory capacity on proteins. Crotonyl-CoA, derived from amino acid catabolism, fatty acid β-oxidation, and gut microbial metabolites, directly modulates crotonylation levels, positioning this modification as a key metabolite sensor. Crotonylation extensively modifies both histones and non-histone proteins, participating in transcription, DNA repair, autophagy, ferroptosis, and metabolic regulation. Dynamic crosstalk with SUMOylation, ubiquitination, and acetylation forms regulatory switches that control genome stability and disease progression. In cancer, crotonylation drives metabolic reprogramming, radio-/chemoresistance, remodeling of the tumor microenvironment, and immune evasion, making it a key and vulnerable therapeutic target. Emerging evidence highlights the involvement of crotonylation in modulating immunotherapy responses and ferroptosis, further expanding its therapeutic relevance. Recent advances in chemical biology and deep learning-such as covalent binders, SiTomics photo-crosslinking probes, and predictive models (e.g., nhKcr, Adapt-Kcr)-enable precise detection and functional interrogation of crotonylation in living cells and clinical samples. Crotonylation marks in clinical specimens show potential as diagnostic and prognostic biomarkers. This review highlights these emerging concepts and discusses the therapeutic potential of targeting crotonylation "writers", "erasers", and "readers" for future precision medicine.
Cai W, Xiao C, Xin Y
… +8 more, Wang D, Deng Z, Liu Y, Li J, Liao T, Yin H, Li C, He J
Cancer Lett
· 2026 May · PMID 42140344
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Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, primary and acquired resistance, driven largely by tumor cell-mediated remodeling of the immunosuppressive tumor microenvironment (TME), li...Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, primary and acquired resistance, driven largely by tumor cell-mediated remodeling of the immunosuppressive tumor microenvironment (TME), limit durable responses in most patients. The cohesin subunit RAD21 exhibits frequent copy number variation (CNV) across human cancers, yet its role in modulating tumor immunity remains poorly defined. Here, we identify RAD21 as a frequently amplified oncogene that promotes tumor cell proliferation and metastasis and whose elevated expression correlates with poor patient survival. Mechanistically, RAD21 drives M2-like polarization of tumor-associated macrophages (TAMs) via upregulation of CSF1 signaling, thereby fostering an immunologically "cold" tumor and conferring resistance to anti-PD-1 therapy. RAD21 depletion reverses this immunosuppressive phenotype and, when combined with anti-PD-1 blockade, achieves maximal tumor regression. Our findings unveil a previously unrecognized oncogenic mechanism wherein RAD21 orchestrates immune evasion through activation of CSF1 signaling and position RAD21 as a promising therapeutic target to overcome resistance to anti-PD-1 blockade.
Larroquette M, Sarnow K, Meloni M
… +14 more, Rudewicz J, Dartigues B, Epinette E, Guyon J, Larrieu CM, Solda G, Bjerkvig R, Engelhardt J, Martin OCB, Bello L, Nikolski M, Heiland DH, Rossi M, Daubon T
Cancer Lett
· 2026 Aug · PMID 42134492
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Cancer Lett
· 2026 Aug · PMID 42134491
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Bispecific antibodies (BsAbs), designed to recognize two different antigens or two different epitopes on the same antigen, are generated in laboratories using various techniques, including chemical conjugation (introduce...Bispecific antibodies (BsAbs), designed to recognize two different antigens or two different epitopes on the same antigen, are generated in laboratories using various techniques, including chemical conjugation (introduced in the 1960s), cell fusion (introduced in the 1980s), and protein engineering (first introduced around the 1990s). The activity of BsAbs is dependent on how the two co-targets are strategically selected; BsAbs can be designed to redirect immune cells or block signaling pathways and to deliver therapeutic activities spatiotemporally to where they are needed. BsAbs are revolutionizing treatment of cancer and other diseases. As of this writing, at the beginning of 2026, 16 BsAbs and 1 BsAb-like fusion protein are approved in the US and/or China, of which 15 are for cancer treatment and 2 are for non-cancer indications, and many more BsAbs are in clinical trials. Next-generation BsAb development is transitioning from traditional wet-lab approaches to artificial intelligence (AI)-powered platforms. AI-assisted tools are poised to facilitate the identification of new targets, predict protein structures, and guide the development of promising new BsAb formats for the treatment of cancer and other diseases.