Molecular Cancer[JOURNAL]
Sun
200 papers
Insight of immune checkpoint blockades in melanoma: mechanism and clinical translation.
Zhang Q, Yuan C, Zhu L … +8 more , Zheng S, Xu Y, Che X, Xiao S, Liu J, Liu H, Li H, Chen X
Mol Cancer · 2026 Jun · PMID 42249376 · Full text
Melanoma, a malignant tumor originating from melanocytes, accounts for only 4% of all skin cancers but is responsible for 75% of skin cancer-related deaths. In recent years, its incidence has steadily increased. Targeted...
Melanoma, a malignant tumor originating from melanocytes, accounts for only 4% of all skin cancers but is responsible for 75% of skin cancer-related deaths. In recent years, its incidence has steadily increased. Targeted therapies and immunotherapies have made significant strides, emerging as the most effective treatments for metastatic melanoma. Immune checkpoint blockades (ICBs) have become a central component of systemic therapy for advanced melanoma. However, their clinical use is limited by immune-related toxicities, primary and acquired resistance, and marked inter-patient heterogeneity in response. As a result, personalized treatment approaches are urgently needed. This paper provides a comprehensive review of recent advancements in melanoma immunotherapy, synthesizing findings from existing research and clinical trials. It highlights the progress made in understanding various immune checkpoints in melanoma and the outcomes of clinical trials involving different ICBs. The aim is to inform clinicians and patients about the latest developments in ICBs therapy while underscoring the critical role of personalized medicine in addressing the diverse needs of patients. Ultimately, the research seeks to catalyze further exploration and innovation in melanoma treatment.
Deconstructing cancer in 3D: models, mechanisms, and personalized solutions.
Huang Z, Duan X, Ji J … +4 more , Cai Q, Jin P, Yu B, Zhang J
Mol Cancer · 2026 Jun · PMID 42249357 · Full text
Three-dimensional (3D) cancer models, notably patient-derived organoids (PDOs), address the critical limitations of traditional preclinical systems, including two-dimensional (2D) monolayer cultures and patient-derived x...
Three-dimensional (3D) cancer models, notably patient-derived organoids (PDOs), address the critical limitations of traditional preclinical systems, including two-dimensional (2D) monolayer cultures and patient-derived xenografts (PDXs), by better recapitulating physiological tumor architecture and patient-specific heterogeneity, thereby revolutionizing oncology research. We chart the complementary technological landscape, from high-fidelity PDOs and scalable spheroids to engineered systems that reconstruct the tumor microenvironment (TME) via co-culture, organ-on-a-chip, and 3D bioprinting. Beyond foundational biology, these tools are driving functional precision medicine, where PDO avatars predict clinical drug response, and accelerating drug discovery through physiologically relevant screening. A core focus is their unparalleled utility in modeling therapy resistance, enabling the induction and multi-omic dissection of resistant clones, deconstructing stroma-mediated protection, and testing rational combination therapies to overcome relapse. Despite challenges in standardization and complete TME integration, the convergence of 3D models with single-cell omics, CRISPR screening, and artificial intelligence heralds a new era of predictive oncology. Ultimately, rigorous validation and clinical translation of these models promise to bridge the gap between bench and bedside, enabling truly personalized and effective cancer therapies.
Histone modifications across cancers: mechanisms, therapy and clinical translation.
Lu P, Chan YT, Kwok CF … +10 more , Li Q, Jiang Z, Xu L, Feng Z, Yuan H, Zou J, Xun Y, Fong TL, Che CM, Wang N
Mol Cancer · 2026 Jun · PMID 42243927 · Full text
Cancer continues to be a major cause of death across the globe, and epigenetic dysregulation, including histone modifications, has been recognized as a major hallmark of cancer development, heterogeneity, and drug resist...
Cancer continues to be a major cause of death across the globe, and epigenetic dysregulation, including histone modifications, has been recognized as a major hallmark of cancer development, heterogeneity, and drug resistance. This review seeks to offer an overview of histone modifications in cancer, including the more studied histone modifications such as acetylation and methylation, as well as the less explored histone modifications such as phosphorylation, ubiquitination, and glycosylation. It also examines the role of histone modifications in the dysregulation of the three categories of enzymes: the writers, the erasers, and the readers, in the development of cancer, including solid tumors and hematological malignancies. This review also further explores the complex crosstalk between histone modifications, DNA methylation, non-coding RNA, and metabolic reprogramming, focusing on the complex epigenetic networks that maintain oncogenic states and confer plasticity to cancer. In terms of the development of new therapeutic agents, recent advances in epigenetic drugs such as HDAC inhibitors, EZH2 inhibitors, and BET inhibitors are also reviewed, as are new therapeutic avenues such as PROTACs, dual inhibitors, and natural epigenetic modulators. It also emphasizes the fact that the expression of histone modifying enzymes is a key change underlying oncogenic transcriptional states in all cancers. Some of the new aspects of epigenetics revealed in the review include the context-dependent role of H3K27me3 and H2BK120ub modifications, the therapeutic potential of epigenetic targets such as EZH2 and BRD4, and the therapeutic potential of combining epigenetic therapy with chemotherapy and immunotherapy.
Radionuclide‑drug conjugates in lung cancer: advances in precision therapy and clinical translation.
Liu J, Zuo X, Yang X … +3 more , Wang X, Gan L, Xue J
Mol Cancer · 2026 Jun · PMID 42243842 · Full text
PURPOSE: Lung cancer is the leading cause of cancer‑related mortality worldwide. Current therapies continue to face challenges such as drug resistance and tumour heterogeneity. Radionuclide‑drug conjugates (RDCs) represe...
PURPOSE: Lung cancer is the leading cause of cancer‑related mortality worldwide. Current therapies continue to face challenges such as drug resistance and tumour heterogeneity. Radionuclide‑drug conjugates (RDCs) represent an emerging theranostic platform designed to precisely irradiate tumours. This review aims to systematically outline the landscape of advances in RDCs for lung cancer, and provides a forward‑looking perspective on next‑generation RDCs. METHODS: This analysis was based on preclinical and clinical data retrieved from PubMed and ClinicalTrials.gov, with all records reviewed up to January 2026. Studies were exhaustively surveyed across most radionuclides relevant to RDCs in lung cancer, following the periodic table to ensure comprehensive coverage. RESULTS: In lung cancer, a total of 66 RDCs have been screened, with 30 having entered early‑phase clinical trials. Among completed trials, RDCs underwent a transition from initial I/Y‑labelled antibodies toward Lu‑labelled somatostatin receptor (SSTR)‑targeting peptides. SSTR remains the dominant target, with a notable shift from agonists to antagonists. Meanwhile, fibroblast activation protein (FAP), epidermal growth factor receptor (EGFR), and programmed death‑ligand 1 (PD‑L1) are receiving growing attention. Peptides and antibodies are equally employed, with bispecific antibodies (bsAbs), single‑domain antibodies (sdAbs), and cyclic peptides advancing rapidly. Furthermore, nanoparticles (NPs) offer versatile platforms, and pretargeting or dual‑targeting strategies are being developed to improve both efficacy and safety. Crown chelators and bipyridine derivatives provide more stable chelating options. Although Lu remains the mainstay, α emitters and emerging mixed‑decay radionuclides like Tb are gaining ground. Combination therapies are also being investigated to enable first‑line application. CONCLUSION: Despite recent progress in RDC development, challenges such as off‑target toxicity, radiation resistance, and radionuclide production remain. Next‑generation RDCs hold promise to overcome these barriers by novel radionuclides, personalised dosimetry, multifunctional delivery platforms, and multidrug combination strategies. Collectively, these innovations will propel RDCs into a personalised, precision theranostic platform for lung cancer.
Navigating luminal heterogeneity: etiology-based proteogenomic subtyping for targeted treatment strategies in breast cancer.
Chang YH, Chen YJ, Hong ZJ … +37 more , Hsiao YJ, Lin KT, Liao GS, Su SF, Lin ZS, Chen HW, Han CL, Chen ES, Hsu YC, Chen YM, Fang H, Yang HC, Chen YS, Lin CY, Hsu HE, Lin CH, Jiang PL, Wu PS, Chen CW, Hung CT, Wu E, Chiu WT, Hsing FN, Liu TP, Wang CY, Wang YT, Yeh CW, Liao KH, Robles AI, Rodriguez H, Yang SL, Hung MC, Lu YS, Chen HY, Yu SL, Yu JC, Chen YJ
Mol Cancer · 2026 Jun · PMID 42237381 · Full text
BACKGROUND: Luminal breast cancer is rising rapidly among East Asian women, particularly younger patients, with variable clinical outcome, yet current risk-stratification models inadequately predict early recurrence of u...
BACKGROUND: Luminal breast cancer is rising rapidly among East Asian women, particularly younger patients, with variable clinical outcome, yet current risk-stratification models inadequately predict early recurrence of under-studied young-onset cases. We hypothesize that the interplay between endogenous mutagenic processes and overlooked environmental carcinogen exposure drives molecular diversity, revealing novel etiologic and therapeutic insights. METHODS: We performed integrative proteogenomic profiling of 164 prospective, treatment-naïve early-stage Taiwanese breast cancer patients using whole-exome sequencing, transcriptomics, proteomics, and phosphoproteomics. Functional validation in luminal models confirmed therapeutic vulnerabilities and biomarkers, with an independent cohort (n = 270) used to stratify high-risk recurrence patients. RESULTS: Our integrative proteogenomic analysis revealed distinct molecular etiologies and actionable vulnerabilities. For the first time, mutation signature analysis revealed both environmental carcinogen exposure (DBAC) and endogenous APOBEC mutagenesis as key contributors to poor disease-free survival, particularly in younger patients. A high-mutation-burden, immune-evasive subgroup revealed immunoepigenetic vulnerabilities. DBAC-driven tumors exhibited overexpression of ROS-detoxifying enzymes, DNA-damage checkpoint activation, and suppressed DNA repair pathways, supporting an environmental-genomic cooperative mechanism. APOBEC-associated tumors exhibited upregulation of APOBEC3B/3F/3G, steroid hormone biosynthesis enzymes, and downstream oncogenic signaling, forming an immunotherapy-responsive subtype. Proteomic classification further resolved luminal heterogeneity beyond PAM50, identifying two clinically relevant groups: (1) a young DBAC-proteome subset with suppressed DNA-repair machinery and favorable chemotherapy response; and (2) a recurrence-prone subtype characterized by co-activating ER, PI3K-AKT-mTOR, and CDK4/6/9 signaling. Functional validation demonstrated that selective CDK9 inhibition targeting the p-POLR2A-Ser2 axis significantly outperformed CDK4/6 blockade. Furthermore, a companion panel (HDAC2, ALDH1L2, ARF4, SCAMP3) stratified high-risk recurrence patients in an independent cohort, supporting biomarker-guided therapy for aggressive luminal breast cancer. CONCLUSIONS: This study uncovers environmental mutagenesis as a previously overlooked but critical driver of luminal breast cancer heterogeneity in East Asian patients. We establish a proteogenomics-transformative scheme to guide risk stratification and subtype-specific vulnerabilities, offering a precision oncology strategy for early-stage East Asian breast cancer management.
MiR-494-5p suppresses colorectal cancer metastasis by multi-level targeting of KAT2B, a novel mechanism disrupting KAT2B enhancer-promoter looping, and inhibiting c-JUN-driven pro-metastatic properties.
Chen S, Leupold JH, Patil NS … +4 more , Xu P, Wang X, Hu X, Allgayer H
Mol Cancer · 2026 Jun · PMID 42231335 · Full text
BACKGROUND: Metastatic progression is the primary cause of death in colorectal cancer (CRC). However, the molecular networks governing CRC metastasis remain incompletely understood, representing a critical knowledge gap....
BACKGROUND: Metastatic progression is the primary cause of death in colorectal cancer (CRC). However, the molecular networks governing CRC metastasis remain incompletely understood, representing a critical knowledge gap. MicroRNAs (miRNAs) are key post-transcriptional regulators frequently dysregulated in CRC, yet their role in metastasis, particularly via non-canonical mechanisms, remains largely underexplored. METHODS: In this study, we identify miR-494-5p as a multi-layer master-regulator acting via several, in part previously undescribed, targeting mechanisms towards KAT2B and key molecular processes in CRC metastasis, using different in vitro and in vivo models, chromosome conformation capture, chromatin and RNA immunoprecipitation, GST- and RNA pull-down, gene editing, and further methods to delineate epigenetic miR-action on promoter enhancer looping. Besides, classical methods delineating translational and transcriptional miR-target interactions in cultured CRC and validations in CRC tissue datasets were applied. RESULTS: Low expression of miR-494-5p correlates with poor patient survival, and miR-overexpression inhibits cell migration, EMT, invasion, and metastasis in vivo. Mechanistically, we identify the histone acetyltransferase KAT2B as a multi-level target of miR-494-5p. Importantly, besides direct classical miR-targeting at the mRNA and gene promoter, we unveil a novel epigenetic mechanism whereby nuclear miR-494-5p silences KAT2B transcription by recruiting Argonaute proteins and altering histone modifications (increasing H3K27me3, decreasing H3K27ac/H3K4me1) at a specific KAT2B enhancer, to which miR-494-5p binds. This leads to the disruption of the mediator complex subunit 1 (MED1)-p300-RNA polymerase II (RNAP II) coactivator complex and dissolution of enhancer-promoter looping, as confirmed by Chromosome Conformation Capture (3C). Downstream, KAT2B epigenetically activates the transcription of the AP-1 component c-JUN by maintaining H3K27 acetylation at its locus. Crucially, KAT2B-induced c-JUN transcriptionally upregulates u-PAR/PLAUR, a key effector promoting several aspects of metastasis. c-JUN knockdown phenocopies the anti-EMT action of KAT2B loss or miR-494-5p. Importantly, c-JUN overexpression rescues the metastatic phenotype suppressed by miR-494-5p or KAT2B knockdown in vitro and in vivo, and this is dependent on u-PAR/PLAUR upregulation. CONCLUSIONS: We delineate a novel miR-494-5p/KAT2B/c-JUN/PLAUR regulatory axis, whereby miR-494-5p functions as a multi-level metastatic suppressor by orchestrating translational, transcriptional, and epigenetic silencing of oncogenic KAT2B. This suppresses c-JUN-dependent cascades including u-PAR/PLAUR, suggesting a novel, miR-orchestrated master-regulatory axis in CRC progression and metastasis.
Multimodal sequencing identifies synergistic mechanisms driving resistance to neoadjuvant nivolumab treatment in hepatocellular carcinoma.
Zeng F, Guo J, Zeng Z … +9 more , Zhang VX, Tsui YM, Li PM, Husain A, Zhang Q, Lee JM, Cheung TT, Ho DW, Ng IO
Mol Cancer · 2026 Jun · PMID 42226281 · Full text
The tumor immune microenvironment (TIME) critically modulates therapeutic responses to immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). Relative to the other solid tumors, HCC is characterized by mo...
The tumor immune microenvironment (TIME) critically modulates therapeutic responses to immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). Relative to the other solid tumors, HCC is characterized by more pronounced intratumoral heterogeneity and has comparatively poorer responsiveness to ICI blockade treatment. Importantly, the correlation of the underlying mechanism of TIME and the molecular underpinnings of immunotherapy resistance in HCC remains elusive. Employing an integrative multi-omics approach, including spatially resolved transcriptomics, single-cell and bulk RNA sequencing, and lipidomics, we delineated the spatiotemporal dynamics and mechanistic basis of resistance to anti-PD-1 therapy in HCC. Our analyses revealed a profoundly immunosuppressive TIME in non-responsive patients, marked by sparse immune cell infiltration within the tumor niche, in contrast to the immune-inflamed TIME observed in the responders. Multidimensional profiling further uncovered dysregulated lipogenesis and aberrant lipid accumulation in tumor cells of the non-responder cases. Notably, tumor-associated macrophages (TAMs), exhausted CD8 T cells, and lipid-enriched tumor cells co-localize at the tumor-immune interface, forming a physical and functional barrier that precludes effective immune cell infiltration into the tumor niche. We also identified the pivotal TAM-tumor cell crosstalk via the ADM-RAMP1-EBP signaling axis, orchestrating lipid metabolism reprogramming and contributing to the attenuated PD-1 therapeutic efficacy. Collectively, these findings provide a comprehensive mechanistic framework for anti-PD1 resistance, unveiling actionable biomarkers and a translational vulnerability to enhance precision therapeutics in HCC.
Landscape of T-cell bispecific antibodies in cancer therapy: therapeutic strategies, challenges and future prospection.
Jiao G, Peng H, Yang Y … +6 more , Liu Y, Liu X, Hu Y, Dai Y, Li Z, Zhao Q
Mol Cancer · 2026 Jun · PMID 42226254 · Full text
T-cell bispecific antibodies (TCBs), a specialized subclass of bispecific antibodies (BsAbs), are engineered to simultaneously engage T cells and tumor cells by binding two distinct antigens-or two epitopes on a single a...
T-cell bispecific antibodies (TCBs), a specialized subclass of bispecific antibodies (BsAbs), are engineered to simultaneously engage T cells and tumor cells by binding two distinct antigens-or two epitopes on a single antigen-thereby redirecting cytotoxic T lymphocytes to eliminate malignant cells. These agents enhance anti-tumor immunity through dual mechanisms: direct activation of T cell receptor (TCR)-mediated signaling and modulation of T cell function via immune checkpoint (ICP) pathways. Clinically, TCBs have demonstrated transformative efficacy, particularly in hematologic cancers, heralding a new era in tumor immunotherapy. Despite their therapeutic promise, widespread clinical adoption of TCBs is impeded by significant challenges-including severe immune-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), as well as resistance conferred by the immunosuppressive tumor microenvironment (TME). This review provides a comprehensive analysis of TCBs, encompassing their molecular design, mechanisms of action, and clinical performance across oncology indications. We systematically compare current TCB platforms with respect to therapeutic strategy, structural format selection, safety profiles, and clinical outcomes. Additionally, we critically evaluate the major translational hurdles facing TCB-based therapies and explore emerging solutions-including the development of novel format antibodies, rational combination regimens with immune checkpoint inhibitors or other immunomodulators, the application of artificial intelligence (AI) in de novo antibody design, and antibody drug conjugates (ADCs). In summary, this review not only highlights the current landscape and limitations of TCBs but also outlines actionable strategies to overcome existing barriers-serving as a valuable resource for researchers, clinicians, and biopharmaceutical developers striving to advance the next generation of T-cell redirecting therapies into clinical practice.
CircSPARC promotes esophageal squamous cell carcinoma through an HNRNPC-EPN2 splicing axis that activates Wnt/β-Catenin signaling.
Dai S, Zhang C, Wei Z … +7 more , Liu Y, Wen Y, Chen J, Li X, Wei S, Sun G, Zhao L
Mol Cancer · 2026 May · PMID 42210380 · Full text
BACKGROUND: Persistent activation of the Wnt/β-catenin signaling pathway is a key driver of esophageal squamous cell carcinoma (ESCC) progression. Circular RNAs (circRNAs) have emerged as critical regulators of oncogenic...
BACKGROUND: Persistent activation of the Wnt/β-catenin signaling pathway is a key driver of esophageal squamous cell carcinoma (ESCC) progression. Circular RNAs (circRNAs) have emerged as critical regulators of oncogenic signaling in cancer. However, how circRNAs contribute to the sustained activation of Wnt/β-catenin signaling in ESCC is poorly defined. METHODS: Integrated analysis of self-sequenced and public circRNA datasets revealed elevated expression of circSPARC in ESCC. The functional effects of circSPARC on cell proliferation, migration, and invasion were evaluated through both in vitro and in vivo assays. RNA pull-down, RNA immunoprecipitation (RIP), alternative splicing analysis, RNA antisense purification (RAP), and cell surface protein biotinylation were used to elucidate the molecular mechanism by which circSPARC mediates aberrant Wnt/β-catenin activation in ESCC. RESULTS: This study identifies a circRNA-mediated alternative splicing axis that promotes activation of Wnt/β-catenin signaling and ESCC progression. CircSPARC interacts with HNRNPC, a heterogeneous nuclear ribonucleoprotein involved in RNA processing, to suppress the tumor-suppressive long transcript of epsin 2 (EPN2), thereby impairing clathrin-mediated endocytosis-dependent degradation of the Wnt receptor frizzled 7 (FZD7). This interaction leads to sustained Wnt/β-catenin activation, thus promoting ESCC progression. Conversely, expression of the EPN2 long transcript restores circSPARC silencing-induced inhibition of Wnt/β-catenin signaling and suppresses ESCC cell malignancy both in vitro and in vivo. Clinically, elevated expression of circSPARC in ESCC tissues correlates with poor patient prognosis. CONCLUSIONS: These findings reveal a circSPARC-HNRNPC-EPN2 axis that drives persistent Wnt/β-catenin activation through a mutation-independent mechanism. Targeting this pathway in tumors with high circSPARC expression presents a promising therapeutic strategy.
Multi-omic profiles of neuroendocrine neoplasms of the pancreas: an integrated landscape.
Bevere M, Gkountakos A, Valentinuzzi S … +24 more , De Fabritiis S, Wong CS, De Robertis R, Mattiolo P, Gentiluomo M, Fassan M, Pea A, Crinò SF, Simbolo M, Mafficini A, Campa D, Cingarlini S, Landoni L, Lawlor RT, Salvia R, D'Onofrio M, Milella M, Adsay V, Brosens LA, Heaphy CM, Hong SM, Singhi AD, Scarpa A, Luchini C
Mol Cancer · 2026 May · PMID 42210310 · Full text
Pancreatic neuroendocrine neoplasms (PanNENs) constitute a heterogeneous group of tumors distinguished by substantial variability in morphology, immunophenotype, molecular characteristics, and clinical behavior. In recen...
Pancreatic neuroendocrine neoplasms (PanNENs) constitute a heterogeneous group of tumors distinguished by substantial variability in morphology, immunophenotype, molecular characteristics, and clinical behavior. In recent years, the advent of multiple omics-based methodologies has significantly enhanced our understanding of these neoplasms. Integrating histology and genomics with survival analyses has clarified that the fundamental distinction within this disease spectrum lies between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Furthermore, genomics, transcriptomics, and epigenetic profiling have deepened the granularity of the PanNET landscape, revealing marked differences even within the same diagnostic category, with important clinical implications. For example, DAXX/ATRX mutations, activation of the alternative lengthening of telomeres pathway, BEND2 gene fusions, and an α-cell transcriptional profile are more frequently associated with adverse outcomes. Additional omics approaches, including metabolomics, proteomics, radiomics, and the more recently developed spatially resolved methodologies, are further expanding current knowledge in this challenging field. In this review, we provide an integrated overview of PanNENs, synthesizing insights generated across diverse multi-omics platforms.
NSCLC brain metastases exhibit reduced HLA-I antigen presentation machinery and immune evasion independent of IFNγ signaling defects.
Vilariño N, de Rodas ML, Villalba-Esparza M … +11 more , Rajendran BK, Huang B, Hijazo-Pechero S, Costantini A, Ranjan K, Ramos-Paradas J, Lu BY, Nadal E, Goldberg SB, Nguyen DX, Schalper KA
Mol Cancer · 2026 May · PMID 42210261 · Full text
BACKGROUND: Patients with lung cancer brain metastases can benefit from immune checkpoint inhibitors (ICI). However, intracranial responses are often limited and not always concordant with activity seen in extracranial d...
BACKGROUND: Patients with lung cancer brain metastases can benefit from immune checkpoint inhibitors (ICI). However, intracranial responses are often limited and not always concordant with activity seen in extracranial disease. Defects in IFNγ signaling and HLA class-I antigen presentation machinery (APM) on malignant cells can drive immune evasion and ICI resistance, and have traditionally been viewed as interdependent. The possible role of these alterations in non-small cell lung cancer (NSCLC) brain progression remains poorly understood. METHODS: Using multiplex quantitative immunofluorescence, we measured and spatially mapped IFNγ signaling markers (pSTAT1 and IRF1) and multiple HLA class-I APM components (β2M, PSMB8, PSMB9, PSMB10, TAP1, TAP2, Tapasin, Calreticulin, and ERp57) in cancer cells and neighboring non-malignant stromal cells from two patient cohorts, including primary tumors, intra- and extra-cranial NSCLC metastases. We also studied tumor-infiltrating lymphocyte (TILs) subpopulations in the cohorts, performed whole transcriptomic analysis of parental human NSCLC H2030 cells and their brain metastatic counterpart H2030-BrM3, and expanded the results using spatial transcriptomics of human tumors. RESULTS: We found comparable levels of IFNγ signaling markers in primary and metastatic lesions and marked downregulation of multiple APM components in metastases, some of which were restricted to the brain. Downregulation of HLA class-I APM components was associated with reduced effector TILs and worse survival. Analysis of human parental H2030 and brain metastatic H2030-BrM3 lung adenocarcinoma cells showed comparable signaling responses after IFNγ stimulation and reduced HLA class-I APM markers in metastatic cells. Transcriptomic analysis of primary/metastatic cells and human tumors identified differential expression of multiple genes associated with HLA class-I APM downregulation. CONCLUSIONS: Our results reveal that APM downregulation is a prominent feature of NSCLC brain metastases, is independent from local IFNγ signaling defects and is associated with unfavorable clinical features. We also identified candidate modulators of the APM pathway in brain metastases with potential translational significance.
Targeting MORC2 activates transposable element-mediated viral mimicry and potentiates immune checkpoint blockade in triple-negative breast cancer.
Zhang FL, Yang SY, Zhang YL … +9 more , Zhao Q, Yang WX, Andriani L, Cai JY, Huang MY, Hu X, Shao ZM, Cao AY, Li DQ
Mol Cancer · 2026 May · PMID 42210236 · Full text
Immune checkpoint blockade (ICB) has shown limited efficacy in triple-negative breast cancer (TNBC), highlighting the need to elucidate mechanisms of immune evasion and identify novel therapeutic targets. Here, we identi...
Immune checkpoint blockade (ICB) has shown limited efficacy in triple-negative breast cancer (TNBC), highlighting the need to elucidate mechanisms of immune evasion and identify novel therapeutic targets. Here, we identify MORC family CW-type zinc finger 2 (MORC2), an ATP-dependent chromatin remodeler, as a key epigenetic suppressor of antitumor immunity in TNBC. MORC2 is significantly upregulated in TNBC and correlates with an immunosuppressive tumor microenvironment and poor response to ICB. Genetic ablation of MORC2 inhibited tumor growth in immunocompetent but not immunodeficient mice, accompanied by enhanced CD8 T cell cytotoxicity and M1-like macrophage polarization. Mechanistically, MORC2 cooperated with the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to deposit histone H3 lysine 9 trimethylation (H3K9me3) repressive marks at transposable elements (TEs), thereby silencing their expression and suppressing viral mimicry through inhibition of endogenous nucleic acid-sensing pathways and interferon responses. Furthermore, SETDB1 methylated MORC2 at residues K234 and K643 to enhance its stability, thus establishing a positive feedback loop that reinforces epigenetic silencing. Importantly, therapeutic targeting of MORC2 using antisense oligonucleotides (ASOs) synergized with anti-PD-1 therapy to suppress tumor growth in mouse TNBC models. Clinically, MORC2 expression inversely correlated with CD8 T cell infiltration and activation in human TNBC samples. Collectively, our findings establish MORC2 as a novel epigenetic immune checkpoint and highlight its therapeutic potential to overcome ICB resistance in TNBC.
AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
Pattanayak SP, Darawshi O, Hajihassani O … +15 more , Winter JM, Weiler N, Ott M, Rothweiler F, Cinatl J, Michaelis M, Lindner DJ, Green TD, Krassovskaia P, Aruleba RT, Fisher-Wellman KH, Mears JA, Wald D, Eriksson LA, Tirosh B
Mol Cancer · 2026 May · PMID 42204603 · Full text
BACKGROUND: mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 an...
BACKGROUND: mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 and TBC1D7. Small molecules that activate mTOR by blocking the TSC are lacking. METHODS: We applied in silico docking and medicinal chemistry to generate AcTor, a potential first-of-its-kind TSC2 inhibitor. Because inhibition of TSC2 results in increased sensitivity to proteasome inhibitors, we combined AcTor and the proteasome inhibitor ixazomib (IXZ) in various cancer cell types. RESULTS: Potentiation of cytotoxic activity of IXZ by AcTor was observed across multiple acute myeloid leukemia (AML) cell lines and primary patient samples. The combination triggered a collapse of mitochondrial respiratory capacity, loss of mitochondrial membrane potential, accumulation of ROS and apoptosis. These attributes increased in drug-resistant AML. Transcriptomic profiling revealed that AcTor alone induced anabolic and oxidative phosphorylation programs, whereas AcTor/IXZ redirected the signaling towards stress-associated and pro-apoptotic transcriptional states, including a p53 pathway signature. In vivo studies revealed reduction in AML burden, depletion of blasts and of leukemic stem cells, and retention of activity upon relapse. AcTor/IXZ was equally potent in a TP53-mutated patient-derived xenograft model, exceeding the efficacy of standard-of-care. CONCLUSIONS: As a TSC2 inhibitor, AcTor should not be used alone in cancer. When combined with proteasome inhibitors, the pharmacodynamics of AcTor shifts towards the development of a mitochondrial catastrophe in AML, which is durable, broad range, agnostic to TP53 mutations and to the acquisition of resistance to common clinical anti-AML drugs.
The mycobiome, virome and archaeome in gastrointestinal cancers: molecular pathogenesis and therapeutic intervention.
Cheng CH, Wong CC
Mol Cancer · 2026 May · PMID 42204538 · Full text
Gastrointestinal (GI) cancers remain a significant global health challenge. For decades, research has concentrated on the bacterial microbiome's role in tumour development, largely neglecting the important roles of the n...
Gastrointestinal (GI) cancers remain a significant global health challenge. For decades, research has concentrated on the bacterial microbiome's role in tumour development, largely neglecting the important roles of the non-bacterial kingdoms, including mycobiome (fungi), the virome (viruses), and archaeome (archaea). These elements represent an underexplored and crucial "dark matter" of the microbiome. This review aims to systematically summarize current evidence on the compositional alterations of viruses, fungi, and archaea across the major types of GI cancer, including colorectal, hepatocellular, gastric, pancreatic and esophageal/oral cancers. We critically examine how viruses, fungi, and archaea directly affect host cellular processes and indirectly influence cancer risk through complex cross-kingdom interactions with the bacterial microbiota and the host immune system. Additionally, we explore the significant translational potential of this knowledge, emphasizing opportunities to use these non-bacterial communities in developing new diagnostic biomarkers and therapeutic strategies. Finally, we highlight the importance of future multi-kingdom integrative analyses to fully understand the microbial ecosystem involved in GI oncogenesis and to translate these insights into clinical practice.
A sweet danger: the silent link between hyperinsulinemia and gastric cancer.
Laurenziello P, Luongo M, Lospinoso Severini F … +4 more , Russi S, Falco G, Calabrese C, Laurino S
Mol Cancer · 2026 May · PMID 42185920 · Full text
Hyperinsulinemia (HI), a compensatory response to insulin resistance commonly associated with obesity and preceding Type 2 Diabetes Mellitus, represents a critical link between metabolic dysfunction and both cancer risk...
Hyperinsulinemia (HI), a compensatory response to insulin resistance commonly associated with obesity and preceding Type 2 Diabetes Mellitus, represents a critical link between metabolic dysfunction and both cancer risk and progression. While its systemic effects are well-documented, its specific impact on gastric cancer (GC) risk and prognosis requires deeper investigation. HI promotes oncogenesis by activating the PI3K/AKT and MAPK/ERK signaling pathways, which are often dysregulated in GC through the overexpression of insulin receptor isoform A as well as oncogenic mutations in their key regulatory proteins, leading to increased cell proliferation, angiogenesis, and therapy resistance. In addition, the intricate crosstalk between these cascades and other signaling pathways, including NF-kB, JAK/STAT, WNT/β-catenin, fosters a pro-inflammatory milieu, the transition to mesenchymal phenotype, and tumor microenvironment remodeling. This review synthesizes two decades of research to elucidate the biochemical mechanisms by which elevated insulin levels provide the necessary stimuli and metabolic energy for tumor survival. We further evaluate clinical management strategies, emphasizing the potential of dietary interventions and pharmacological approaches to modulate the course of disease. Notably, a meta-analysis of existing literature indicates that metformin use is strongly associated with a reduced GC risk (Hazard Ratio, HR: 0.67, p = 0.008), and better outcomes including lower recurrence (HR: 0.61, p < 0.0001), all-cause mortality (HR: 0.61, p = 0.0002), and cancer-specific mortality (HR: 0.80, p = 0.0003). Despite the limitations of our findings, our review indicates that the pharmacological control of HI, and the underlying mutational pattern and pathway alterations it promotes, should be considered relevant in oncological management of GC patients.
Hallmarks of epithelial-mesenchymal plasticity in cancer.
Clauzon L, Verona F, Shams K … +5 more , Brancato OR, Di Bella S, Di Miceli N, Stassi G, Di Franco S
Mol Cancer · 2026 May · PMID 42185888 · Full text
Cancer stem cells (CSCs) drive tumour initiation, progression, metastasis, and therapy resistance through their remarkable plasticity, enabling dynamic transitions between stem-like and differentiated states. A pivotal m...
Cancer stem cells (CSCs) drive tumour initiation, progression, metastasis, and therapy resistance through their remarkable plasticity, enabling dynamic transitions between stem-like and differentiated states. A pivotal mechanism underlying this plasticity is epithelial-mesenchymal plasticity (EMP), which encompasses epithelial-mesenchymal transition (EMT), partial or hybrid EMT (E/M) states, and mesenchymal-epithelial transition (MET), allowing cancer cells to acquire invasive, stem-like properties while maintaining proliferative potential. Unlike the traditional binary view of EMT, recent evidence reveals a spectrum of intermediate E/M phenotypes that exhibit increased tumorigenicity, metastatic potential, and therapy resistance. This plasticity is orchestrated by intricate regulatory networks involving EMT-inducing transcription factors, signalling pathways, and non-coding RNAs. The tumour microenvironment (TME), with its cellular and non-cellular components, provides critical extrinsic cues that stabilize E/M states. Notably, metabolic reprogramming cooperates with EMP. Indeed, E/M flexibly shifts between glycolysis, oxidative phosphorylation, and lipid metabolism alterations to fuel invasion, buffer oxidative stress, and evade ferroptosis. Advanced and recently developed in vitro and in vivo models have illuminated these dynamics: dual-fluorescent reporters, microfluidic tumour-on-a-chip, genetically engineered mouse models, bioluminescence imaging, and intravital microscopy enable real-time tracking of EMP during progression and therapy response. On the other side, in silico tools, single-cell/spatial transcriptomics, network inference, machine learning, and agent-based modelling, map hybrid states, predict trajectories, and help identify biomarkers, revealing EMP's role in evolutionary fitness. Therapeutically, targeting EMP holds promise to target resistant cancer cells and prevent relapse, though challenges arise from redundancy and plasticity. Strategies include pathway inhibitors, metabolic disruptors, epigenetic agents, TME modulators, and differentiation inducers. Combination therapies, guided by EMP biomarkers and rational models, act in combination with standard treatments to lock cells in epithelial states, disrupt hybrid phenotypes, and overcome resistance. This review highlights EMP as the main driver of tumour evolution, offering a unified framework for understanding tumour heterogeneity and heterogeneity-driven failures in therapy. By elucidating molecular mechanisms and vulnerabilities, it paves the way for precision interventions that could transform outcomes in aggressive malignancies, ultimately restraining metastasis and recurrence.
SUMOylation in cancer: molecular mechanisms and therapeutic implications.
Ding Y, Li F, Wang JM
Mol Cancer · 2026 May · PMID 42185884 · Full text
Small Ubiquitin-like Modifier modification (SUMOylation), a critical post-translational modification, plays a dual role in cancer by regulating both tumor cell-intrinsic properties and the tumor immune microenvironment (...
Small Ubiquitin-like Modifier modification (SUMOylation), a critical post-translational modification, plays a dual role in cancer by regulating both tumor cell-intrinsic properties and the tumor immune microenvironment (TIME). Based on a synthesis of direct mechanistic, functional/preclinical, and correlative evidence, it promotes immune evasion through multiple mechanisms: suppressing antigen presentation, limiting immunopeptidome diversity, regulating immune checkpoint molecules (with direct evidence for PD-L1 and TIGIT, while support for other checkpoints remains indirect), and modulating immune cell differentiation and function. Pharmacological inhibition of SUMOylation (e.g., TAK-981, ML792) reverses these immunosuppressive effects by restoring antigen presentation, activating type I interferon responses, enhancing CD8 + T cell cytotoxicity, and reducing regulatory T cells. Notably, while prospective validation is still lacking, SUMOylation-related gene signatures hold promise as prognostic markers and correlative candidate indicators of immunotherapy response. Furthermore, preclinical models demonstrate that SUMOylation inhibitors synergize with immune checkpoint blockade to enhance anti-tumor efficacy, although this synergistic effect has not yet been validated in clinical settings. This review consolidates current knowledge on the immunologic and translational dimensions of SUMOylation-from molecular mechanisms to therapeutic implications-into a single narrative focused on how SUMOylation shapes the TIME and its implications for cancer immunotherapy.
Beyond Darwin: reactive heredity, burst-drift dynamics and eco‑evolutionary control of cancer.
Lagache L, Salzet J, Fournier I … +1 more , Salzet M
Mol Cancer · 2026 May · PMID 42174661 · Full text
Darwinian clonal evolution provides a necessary framework for understanding tumour progression, yet emerging evidence shows that some cancers depart from a strictly gradualist tempo through episodic "macroevolutionary" l...
Darwinian clonal evolution provides a necessary framework for understanding tumour progression, yet emerging evidence shows that some cancers depart from a strictly gradualist tempo through episodic "macroevolutionary" leaps. We propose a unifying Burst-Drift-Control (BDC) model in which short-lived genomic reconfigurations ("bursts") that transiently alter heritable genomic states ("reactive heredity") precede longer intervals of constrained expansion, creating time-bounded vulnerabilities that clinicians may strategically steer ("control"). In this usage, the Drift component refers specifically to a drift-dominated or weak-selection interval after any initial post-burst sorting, not to the selective sweep itself. In the Burst phase, single catastrophic events, such as extrachromosomal DNA amplifications, chromothripsis, chromoplexy or whole-genome doubling, can generate major shifts in genotype and phenotype. These bursts produce new genetic configurations and can increase evolvability, for example when ecDNA circles permit oncogene dose tuning and non-Mendelian inheritance. During the drift-dominated interval, tumours may enter longer periods of constrained or near-neutral expansion in which spatial structure, clonal interference and weak or unresolved selection allow multiple lineages to persist, although the prevalence of such dynamics varies substantially by tumour type and treatment context. BDC does not assume that selective advantage is higher immediately after a burst than at later time points; later therapy or microenvironmental change can also impose strong selection. Finally, in the Control phase, if therapy is timed to exploit ecological dependencies and the fitness costs of resistance, cancer growth may be restrained as a stable, polyclonal "oligopoly" rather than progressing rapidly to an aggressive monoclonal takeover. We discuss supporting evidence, counterexamples and practical limitations, and argue that the main value of BDC lies in linking punctuated genome change to testable windows for evolutionary steering.
JAK-STAT signaling pathway in cancer: from molecular mechanisms to clinical intervention.
Zhang X, Li P, Ma F … +6 more , Wang T, Chu Q, Wei S, Xue C, Wang Z, Lu J
Mol Cancer · 2026 May · PMID 42169118 · Full text
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a conserved signaling network that mediates communication between extracellular cytokine stimulation and nuclear transcrip...
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a conserved signaling network that mediates communication between extracellular cytokine stimulation and nuclear transcriptional responses. Beyond its established role in regulating cell proliferation, differentiation, immune responses, and tissue homeostasis, dysregulated JAK/STAT signaling contributes to tumor progression, immune evasion, therapeutic resistance, and remodeling of the tumor microenvironment (TME). Although canonical ligand-dependent JAK/STAT activation has been extensively characterized, increasing evidence indicates that STAT proteins also participate in diverse non-canonical signaling processes, including organelle-associated localization, liquid-liquid phase separation, epigenetic regulation, and JAK-independent activation. These mechanisms expand the functional complexity and context dependence of JAK/STAT signaling in cancer biology. Within the TME, persistent pathway activation modulates dynamic interactions among tumor cells, immune cells, and stromal components, thereby promoting immunosuppressive signaling networks and therapeutic resistance. In this review, we summarize current understanding of canonical and non-canonical JAK/STAT signaling mechanisms, regulatory networks governing pathway activation, and the multifaceted roles of JAK/STAT signaling in tumor progression and therapeutic resistance. We further discuss emerging therapeutic strategies targeting the JAK/STAT pathway, including selective kinase inhibitors, STAT-directed therapies, epigenetic modulators, and combination immunotherapeutic approaches, together with the major translational challenges that continue to limit clinical efficacy.
CTHRC1 drives megakaryocyte-mediated immunotherapy resistance in esophageal squamous cell carcinoma via the integrin αIIbβ3/Rap1 pathway and is targetable by mRNA vaccination.
Liu Y, Zhou J, Song M … +12 more , Wang J, Shang Q, Du J, Li Y, Chen X, Wang J, Liao X, Chen L, Li W, Yuan Y, Yang Y, Wu Y
Mol Cancer · 2026 May · PMID 42169077 · Full text
The clinical efficacy of immunotherapy in advanced esophageal squamous cell carcinoma (ESCC) remains suboptimal, as most patients eventually develop drug resistance and experience disease progression. Here, we identify C...
The clinical efficacy of immunotherapy in advanced esophageal squamous cell carcinoma (ESCC) remains suboptimal, as most patients eventually develop drug resistance and experience disease progression. Here, we identify Collagen Triple Helix Repeat Containing 1 (CTHRC1) as a critical mediator of immunotherapy resistance in ESCC. Elevated CTHRC1 expression was observed in tumors unresponsive to immune checkpoint blockade and was associated with enhanced platelet activity and infiltration of megakaryocytes (MKs) into the tumor microenvironment. Mechanistically, CTHRC1 facilitated MK activation and recruitment, fostering an immunosuppressive niche that impaired cytotoxic T-cell activity and promoted cell exhaustion. To therapeutically target this axis, we developed a lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding CTHRC1. In preclinical ESCC models, the CTHRC1-mRNA-LNP vaccine elicited robust antitumor immunity. Notably, the combination of CTHRC1-mRNA vaccination with anti-PD-1 therapy induced synergistic intratumoral T-cell infiltration, depletion of MKs, reversal of immunosuppression, and durable tumor regression. Collectively, these findings uncover an unrecognized immunoregulatory function of CTHRC1 in ESCC and highlight its therapeutic targeting as a promising strategy to enhance the efficacy of immune checkpoint blockade.
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