Molecular Cancer[JOURNAL]
Sun
200 papers
Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.
Pardo L, Moore M, Deshmukh R … +22 more , Powley I, Waldron JA, Kruspig B, McGarry L, Dolma L, Campos AV, Wood C, Leslie H, Hughes M, Jeldes E, Munro J, Mitchell L, Officer-Jones L, Baird R, Coquelet H, Jamieson NB, Sumpton D, Strathdee D, le Quesne J, Bushell M, Murphy DJ, Norman JC
Mol Cancer · 2026 May · PMID 42163342 · Full text
BACKGROUND: Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations i...
BACKGROUND: Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations in mRNA translation during early tumorigenesis affect tumour development in KRAS-driven lung adenocarcinoma (LuAd). METHODS: We deployed autochthonous mouse models of LuAd driven by oncogenic KRAS combined with moderate overexpression of MYC and simultaneously manipulated mRNA translation by deleting the mRNA helicases eIF4A1 and eIF4A2 or by administering pharmacological inhibitors of protein synthesis, such as rapamycin. This permits synchronous assessment of LuAd initiation and progression in vivo and is amenable to parallel ex vivo culture of tumour-derived cells for detailed analysis of protein synthesis (using ribosome footprinting) and metabolic landscapes. These approaches also allowed us to perform multiplex imaging and spatial transcriptomics to characterise tumour formation in altered mRNA translation conditions and to compare results obtained in mice against the Lattice-A cohort of non-small cell lung cancer (NSCLC) patients. RESULTS: Deletion of the mRNA-translation repressor, eIF4A2 in KRAS-driven LuAd leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics. Paradoxically, this overdriven secretory protein synthesis landscape delays tumorigenesis and leads to the appearance of clusters of non-proliferative, p21-positive KRAS-expressing cells in the lung. Consistently, reduction of mRNA translation with rapamycin in Eif4a2-deleted tumours suppresses senescence and restores tumorigenesis. Importantly, some Eif4a2 knockout cells overcome senescence to form tumours that exhibit enhanced MAP-kinase signalling and, in contrast to eIF4A2 lesions, these were eradicated by administration of a MEK inhibitor. Consistently, MAP-kinase signalling was significantly increased in human NSCLC expressing low levels of eIF4A2. CONCLUSIONS: Our study highlights that restraint of mRNA translation by eIF4A2 is critical in the early-stages of KRAS-driven LuAd to allow bypass of oncogene-induced senescence and tumour progression. Importantly, because tumours with dysregulated mRNA translation rely heavily on MAP-kinase signalling they are exquisitely sensitive to MEK inhibition, and this indicates the possibility that low expression of eIF4A2 could be used to identify potential responders to MEK inhibitors in clinical trials.
The Treg-cell death axis in lung cancer: implications for immune evasion and novel therapeutic strategies.
Fan W, An Q, Wang X … +8 more , Qin D, Zhao Z, Dong X, Wang L, Wong AL, Yang DH, Goh BC, Dong J
Mol Cancer · 2026 May · PMID 42163322 · Full text
Regulatory T cells (Tregs) are central mediators of immune tolerance and key drivers of tumor immune evasion in non-small cell lung cancer (NSCLC). Within the tumor microenvironment (TME), Tregs accumulate and suppress a...
Regulatory T cells (Tregs) are central mediators of immune tolerance and key drivers of tumor immune evasion in non-small cell lung cancer (NSCLC). Within the tumor microenvironment (TME), Tregs accumulate and suppress antitumor responses, thereby limiting the durability of immune checkpoint inhibitor (ICI) responses. Emerging evidence indicates that Treg influence on immunotherapy outcomes extends beyond numerical abundance to involve a dynamic Treg-cell death axis, in which enhanced Treg survival and resistance to regulated cell death are coupled with dysfunction, exhaustion, or attrition of effector T cells. Tumor-derived chemokines, cytokines, and metabolic cues promote recruitment, stabilization, and metabolic fitness of Tregs, enabling their persistence within hypoxic and nutrient-deprived niches. Concurrently, Tregs suppress antigen-presenting cell activation, amplify checkpoint signaling, and exploit metabolic and redox adaptations including ferroptosis resistance to maintain immunosuppressive dominance under therapeutic pressure. Together, these mechanisms establish a survival-advantaged regulatory compartment that drives immune cell-fate asymmetry within the TME and limits the durability of immune checkpoint blockade. We propose the Treg-cell death axis as a unifying framework linking immune tolerance, regulated cell death, and immunotherapy resistance in lung cancer. Targeting this axis through mechanism-matched strategies that destabilize tumor-resident Tregs while preserving systemic immune homeostasis may provide new opportunities to overcome therapeutic resistance and improve clinical outcomes.
Advanced 3D cancer models for analyzing tumor-immune cell interaction and therapeutic response.
Jeevanandan SP, Reidy E, Clegg J … +3 more , Curvello R, Ryan AE, Loessner D
Mol Cancer · 2026 May · PMID 42157225 · Full text
Immunotherapy is transforming the treatment of cancer by activating and directing a patient's own immune response to target tumor cells. In solid tumors, however, there has been limited success in sustaining anti-tumor i...
Immunotherapy is transforming the treatment of cancer by activating and directing a patient's own immune response to target tumor cells. In solid tumors, however, there has been limited success in sustaining anti-tumor immune responses. This is attributed to the intrinsic features of the tumor microenvironment, including the lack of infiltrating immune cells and varying expression of tumor antigens, forming an immunosuppressive landscape. Despite recent advances, we do not fully understand how the immune components of the tumor microenvironment are linked to ineffective treatment outcomes. Advanced 3D cancer models offer a platform to deconstruct tumor tissues and study disease progression and resistance to treatment, helping to uncover drivers of immune evasion in a physiologically relevant context. Here, we discuss aspects of the tumor immune microenvironment in selected solid tumors defined by distinct immunosuppressive features that dictate response to immunotherapy. We highlight how advanced 3D cancer models accelerate the development and screening of therapeutic strategies that target the immunosuppressive microenvironment.
An orally bioavailable pan-αv/α5β1 integrin antagonist prevents aggressive prostate cancer progression via suppressing both oncogenic signals and CD47-mediated immune escape.
Gu Y, Dong B, Teng X … +12 more , Chen L, Yang Y, Sun X, Song S, Qian B, Sun Y, Zhang J, Zheng Z, Chen Y, Cui Y, Rong Z, Pang X
Mol Cancer · 2026 May · PMID 42129801 · Full text
BACKGROUND: Advanced prostate cancer (PCa), particularly enzalutamide-resistant, bone-metastatic castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), remains an intractable clinical chal...
BACKGROUND: Advanced prostate cancer (PCa), particularly enzalutamide-resistant, bone-metastatic castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), remains an intractable clinical challenge due to oncogenic crosstalk across multiple pathways and tumor microenvironment (TME) heterogeneity. Given these unmet clinical needs, novel targeted therapeutics are urgently required to improve advanced PCa patient outcomes. METHODS: In this study, we examined the expression of integrin subtypes, particularly pan-αv integrins and α5β1, in prostate cancertumor samples and cell lines using immunohistochemistry (IHC) and Western blotting. Based on rational drug design, we synthesized a first-in-class, orally bioavailable, non-RGD pan-αv/α5β1 integrin antagonist, C19-9N, and characterized it through homology modeling, molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST). The antitumor activity of C19-9N was evaluated in vitro (via assays of cell viability, migration and invasion) and in vivo using multiple models, including subcutaneous xenografts of CRPC, bone-metastatic xenograft models established by intratibial and intracardiac injection, and patient-derived xenografts (PDXs) of NEPC. The in vivo safety and pharmacokinetic profile of C19-9N were also assessed. Mechanistically, single-cell RNA sequencing (scRNA-seq) was employed to uncover the regulatory effects of C19-9N on infiltrating immune cells within the tumor microenvironment, which were further validated through multiplex immunofluorescence and bone marrow-derived macrophage-mediated phagocytosis assays. RESULTS: C19-9N targeting pan-αv and α5β1 integrin circumvented potential compensatory resistance mediated by integrin subtype switching. C19-9N disrupted extracellular matrix (ECM)-integrin biochemical and mechanical signaling, thereby suppressing cancer stem cell (CSC) self-renewal and epithelial-to-mesenchymal transition (EMT). Mechanistically, C19-9N inhibited PI3K/AKT and STAT3 signaling pathways to block alternative splicing of AR-V7, and modulated Survivin and c-Myc to enhance enzalutamide sensitivity. Additionally, it remodeled TME by repolarizing tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype and downregulating CD47-mediated immune escape. In preclinical models, C19-9N overcame enzalutamide resistance in CRPC xenografts, suppressed bone metastatic progression, and exhibited superior efficacy to platinum/taxane therapies in NEPC. CONCLUSION: Collectively, by co-targeting oncogenic drivers and TME vulnerabilities, C19-9N heralds a transformative therapeutic paradigm with profound clinical potential for aggressive PCa.
From guardians to traitors: molecular mechanisms of tumor-induced T cell betrayal.
Ye P, Kuang H, Lin A … +10 more , Tang B, Wang Q, Zhang H, Wong HZH, Zhang J, Cheng Q, Glaviano A, Yang T, Du H, Luo P
Mol Cancer · 2026 May · PMID 42108449 · Full text
As the core effector cells of the adaptive immune system, T cells play a crucial role in the body's anti-tumor immune responses. However, various toxic factors widely present in the tumor microenvironment (TME), includin...
As the core effector cells of the adaptive immune system, T cells play a crucial role in the body's anti-tumor immune responses. However, various toxic factors widely present in the tumor microenvironment (TME), including metabolic abnormalities, mitochondrial transfer phenomena, and diverse toxic mediators, can exert "poisoning" effects on T cells through complex and diverse mechanisms, consequently leading to T cell intoxication. In this state, their roles within the TME undergo profound transformation, with exhaustion being the most typical manifestation. This exhaustion is characterized by loss of anti-tumor function, metabolic dysfunction, and high expression of inhibitory receptors, thereby exacerbating tumor progression. However, studies have revealed that as tumor poisoning intensifies, certain specialized T cell subsets not only exhibit functional impairment but can also actively promote tumor progression through mechanisms such as cytokine secretion and recruitment of tumor-associated cells-a phenomenon defined as T cell betrayal. This review comprehensively and systematically summarizes the patterns of T cell fate transformation during tumor development and provides an in-depth analysis of the essential characteristics of T cell intoxication and betrayal, including their phenotypic features, functional alterations, and their impact on the tumor microenvironment and immunotherapy. Particular emphasis is placed on analyzing the molecular integrative mechanisms by which tumor cells and other cells in the microenvironment poison T cells and induce their intoxication or betrayal through multiple pathways. Furthermore, this review systematically examines therapeutic strategies for reversing T cell betrayal phenomena, including metabolic intervention and microenvironmental modulation, as well as optimization strategies for conventional immunotherapies. This review further explores future directions for achieving a systematic and holistic understanding of the T cell "intoxication-betrayal" framework and examines the potential application value of cutting-edge technologies in this field, aiming to provide novel insights for tumor immunotherapy.
Organoids in cancer therapy: translational applications and clinical promise.
Bai M, Liu M, Wang S … +9 more , Ran M, Ye J, Xie Y, Zhang C, Wang Y, Lu J, Dai F, Li D, Li H
Mol Cancer · 2026 May · PMID 42106781 · Full text
Cancer remains a leading cause of mortality worldwide, with its management challenged by profound biological complexity and substantial intratumoral and interpatient heterogeneity. Conventional preclinical tumor models f...
Cancer remains a leading cause of mortality worldwide, with its management challenged by profound biological complexity and substantial intratumoral and interpatient heterogeneity. Conventional preclinical tumor models fail to recapitulate key features of the human tumor microenvironment, limiting their translational relevance. Tumor organoids are three-dimensional (3D) culture systems that retain patient-specific tissue architecture and heterogeneity, and have emerged as powerful platforms for translational cancer therapy research. Recent advances in organoid engineering, including microfluidic organoid-on-chip systems, 3D bioprinting, and next-generation biomaterials, have markedly improved physiological relevance, experimental controllability, and scalability. These innovations enable higher-throughput drug screening and more informative functional profiling to support individualized therapeutic decision-making. In parallel, organoid-based predictive modeling frameworks are creating new opportunities to rationally design precision treatment regimens and to elucidate mechanisms underlying therapeutic response and acquired resistance. Importantly, integrating organoid-derived functional readouts with molecular and clinical data is accelerating bench-to-bedside translation and strengthening the evidence base for personalized oncology. Here, we systematically summarize the multidimensional applications of organoids in translational cancer therapy, critically discuss their advantages and current limitations, and outline key directions for future development, with the aim of facilitating the implementation and optimization of precision oncology.
Non-coding RNAs as master regulators of ferroptosis in cancer: mechanisms and clinical implications.
Mo H, Xie Y, Zhang H … +6 more , Liu Y, Wu W, Xia Z, Luo P, Liu Z, Cheng Q
Mol Cancer · 2026 May · PMID 42092949 · Full text
Ferroptosis is a non-apoptotic form of cell death characterized by intracellular iron accumulation and the subsequent elevation of cytotoxic lipid peroxides. Various cellular metabolic pathways intricately regulate this...
Ferroptosis is a non-apoptotic form of cell death characterized by intracellular iron accumulation and the subsequent elevation of cytotoxic lipid peroxides. Various cellular metabolic pathways intricately regulate this process, including redox homeostasis, iron metabolism, lipid metabolism, and other signaling cascades. Increasing evidence substantiates the critical role of ferroptosis in tumorigenesis and cancer therapy. However, our current understanding of numerous mechanisms underlying tumor ferroptosis remains limited. Noncoding RNAs (ncRNAs) provide a new perspective. Several ncRNAs, particularly microRNAs, long noncoding RNAs, and circular RNAs, are being demonstrated to form a comprehensive regulatory network that exerts direct regulation over ferroptosis-related genes or enzymes while indirectly modulating regulatory factors associated with ferroptosis. Strikingly, ncRNAs also serve as crucial mediators orchestrating communication between cancer cells, stromal cells, and immune cells within the tumor microenvironment (TME). Given their substantial potential in tumors and the TME, ferroptosis-related RNAs emerge as promising targets for immunotherapy and overcoming drug resistance. The development of novel nanomedicines for delivering ncRNAs is crucial in advancing antitumor therapy. This review comprehensively elucidates the regulatory mechanisms of ferroptosis-associated ncRNAs across various cancers, sheds light on their functions within the TME, explores their clinical potential to overcome drug resistance, and highlights unresolved questions.
Testosterone and cancers: biological functions, molecular mechanisms and therapy.
Zhou Z, Huang T, Li J … +9 more , Fu L, Xu L, Feng X, Zhang Z, Pan H, Qin K, Zhou X, Xiang Y, Yuan K
Mol Cancer · 2026 May · PMID 42092921 · Full text
Testosterone, the principal androgen in humans, plays an essential role in maintaining physiological homeostasis. In recent years, accumulating evidence has implicated testosterone in the progression of diverse malignanc...
Testosterone, the principal androgen in humans, plays an essential role in maintaining physiological homeostasis. In recent years, accumulating evidence has implicated testosterone in the progression of diverse malignancies, underscoring its context-dependent roles in tumor biology. A series of studies suggest that testosterone can act through canonical androgen receptor (AR) signaling as well as non-canonical, AR-related mechanisms to modulate membrane receptor-mediated signal transduction, metabolic reprogramming, and the tumor immune microenvironment, thereby fostering tumor growth, metastasis, maintenance of stemness, and the development of therapy resistance. Notably, interventional strategies targeting testosterone/androgen signaling have entered clinical investigation and have demonstrated therapeutic promise. Beyond the best-developed clinical paradigms of prostate and breast cancer, we also highlight hepatocellular carcinoma and cutaneous melanoma as informative additional contexts that broaden the understanding of testosterone biology across cancers. Here, we propose that testosterone is best understood not simply as a hormonal input into isolated cancer pathways, but as a systems-level endocrine regulator of tumor plasticity that integrates transcriptional programs, rapid kinase signaling, and membrane receptor-associated responses across distinct tumor contexts. Within this framework, membrane androgen signaling is considered an emerging but still largely preclinical therapeutic vulnerability, whereas androgen-directed interventions in prostate and breast cancer represent the most clinically mature translational paradigms.
Modulation of tumor-derived exosomes and reprogramming of cancer-associated fibroblasts for colorectal cancer therapy.
Han S, Huang T, Yin X … +7 more , Wang T, Shi Q, Tang Y, Zhu T, Gao S, Sui H, Hou F
Mol Cancer · 2026 May · PMID 42092888 · Full text
Hypoxia is pervasive within the solid tumor microenvironment (TME), reshaping it through exosome release. As the main component of the tumor stroma, fibroblasts influence TME remodeling and tumor progression. Recent adva...
Hypoxia is pervasive within the solid tumor microenvironment (TME), reshaping it through exosome release. As the main component of the tumor stroma, fibroblasts influence TME remodeling and tumor progression. Recent advances in targeting tumor-derived exosomes offer promising opportunities for innovative colorectal cancer (CRC) therapies. Here, we found that exosomes induced by hypoxia in CRC cells (H-Exo) can promote the activation of normal tissue-associated fibroblasts (NAFs) into cancer-associated fibroblasts (CAFs) phenotype, with a stronger effect compared to normoxic exosomes (N-Exo). Machine learning analysis identified HIF1A-AS2, induced by hypoxic tumor-derived exosomes, as a promising prognostic lncRNA in CRC. Pan-cancer and scRNA-seq analyses showed that high HIF1A-AS2 expression was characterized by hypoxia, angiogenesis, immunosuppression (e.g., CAFs), TGF-β, and fibroblast-CD44 interactions in CRC. HIF1A-AS2 expression progressively increased along pseudotime, shifting from early immune activation to late-stage extracellular matrix (ECM) organization, vascular niche formation, and fibroblast activation. HIF1A-AS2 in H-Exo was a key factor in the transformation of NAFs into CAFs. Exosomal HIF1A-AS2 sequesters miR-33, thereby derepressing HIF-1α, activating Notch1/ERK signaling, and upregulating angiogenic and matrix-remodeling factors (e.g., VEGF, MMP-7, and MMP-9). Further research revealed that exosomes with silenced HIF1A-AS2 or overexpressed miR-33 could inhibit CAF infiltration, tumor cell proliferation, angiogenesis, and ECM reorganization in xenografts, ultimately suppressing tumor growth. These findings highlight that simultaneously blocking tumor exosome-driven fibroblast activation and the HIF1A-AS2/miR-33/HIF-1α axis may serve as a promising therapeutic avenue for CRC intervention.
Correction: Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.
Zhong H, Pan R, Ouyang Y … +7 more , Xiao T, Gu W, Yang H, Wang H, Li H, Peng T, Chen P
Mol Cancer · 2026 May · PMID 42067927 · Full text
Abstract loading — click title to view on PubMed.
A non-complement role for C1R rewires integrin and death-receptor signaling to drive renal cancer metastasis.
Wei H, Li S, Zhu S … +15 more , Xu C, Wang Y, Li Z, Guan Y, Li J, Jiang R, Ge X, Yi T, Xu X, Xie Y, Tian J, Piao Y, Zhang P, Quan C, Jin X
Mol Cancer · 2026 May · PMID 42067912 · Full text
BACKGROUND: Metastasis is the leading cause of death in clear cell renal cell carcinoma (ccRCC) patients. Anoikis, a form of programmed cell death induced by the loss of cell-extracellular matrix interactions, is a criti...
BACKGROUND: Metastasis is the leading cause of death in clear cell renal cell carcinoma (ccRCC) patients. Anoikis, a form of programmed cell death induced by the loss of cell-extracellular matrix interactions, is a critical factor in hindering metastasis. Nevertheless, the regulatory mechanisms underlying anoikis resistance in ccRCC remain poorly characterized and warrant further investigation. METHODS: We created a single-cell transcriptomic atlas of ccRCC metastasis and used multi-omics data to identify the key role of complement C1R during metastasis. Anoikis-related cell experiments and mouse models were conducted to assess the impact of C1R on anoikis resistance and metastatic potential. Transcriptome sequencing, immunoprecipitation, molecular docking, truncation construction, and immunofluorescence were used to explore how C1R induces anoikis resistance. The mouse lung metastasis model was employed to validate the efficacy of a novel combination drug regimen. RESULTS: Our study identifies complement C1R as a crucial regulator of ccRCC metastasis by enhancing anoikis resistance. ITGB1 and FAF1 have been recognized as crucial downstream targets of C1R. Specifically, C1R promotes anoikis resistance by facilitating ITGB1 endocytosis to activate the Akt/Erk pathway and by inhibiting FAF1-FAS binding to block the Fas/FasL pathway. Moreover, our findings indicate that the combined use of the ITGB1 inhibitor (ATN161) and the Fas/FasL pathway activator (Edelfosine) significantly suppresses ccRCC metastasis. CONCLUSION: C1R functions as a pivotal driver of ccRCC metastasis through dual mechanisms, and therapeutic strategies targeting C1R may offer a promising approach to inhibit metastasis.
Correction: Circular RNA F-circSR derived from SLC34A2-ROS1 fusion gene promotes cell migration in non-small cell lung cancer.
Wu K, Liao X, Gong Y … +7 more , He J, Zhou JK, Tan S, Pu W, Huang C, Wei YQ, Peng Y
Mol Cancer · 2026 May · PMID 42067873 · Full text
Abstract loading — click title to view on PubMed.
Endoplasmic reticulum stress in antitumor immunity and immunotherapy resistance: mechanisms and therapeutic implications.
Zhao Y, Shang Y, Luan T … +7 more , Yu Z, Yue Y, Niu X, Li H, Wang S, Wang C, Liu L
Mol Cancer · 2026 Apr · PMID 42046149 · Full text
Tumor cells utilize various strategies to enable themselves to survive under adverse conditions and to inhibit the development of antitumor immunity. Factors in the tumor microenvironment (TME), e.g., hypoxia, oxidative...
Tumor cells utilize various strategies to enable themselves to survive under adverse conditions and to inhibit the development of antitumor immunity. Factors in the tumor microenvironment (TME), e.g., hypoxia, oxidative stress, and nutrient deprivation, can impair the protein-folding ability of the endoplasmic reticulum (ER) and destroy ER homeostasis both in tumor and immune cells, leading to ER stress. This stress is characterized by the accumulation of misfolded or unfolded proteins. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway controlled by three ER stress sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). In addition to endowing tumor cells with enhanced abilities for tumorigenesis, metastasis, and treatment resistance, aberrant activation of ER stress also impairs antitumor immunity by modulating the phenotype and function of immune cells in the TME. Therapeutic interventions targeting ER stress can achieve direct tumor-killing effects and simultaneously enhance antitumor immune responses. Here we provide a comprehensive overview of the intrinsic and extrinsic mechanisms by which ER stress shapes antitumor immunity and promotes immunotherapy resistance. By understanding these mechanisms, we discuss that ER stress-targeted strategies hold potential to reinvigorate antitumor immunity and improve immunotherapy outcomes. Furthermore, we explore the potential of ER stress as prognostic and predictive biomarkers for cancer immunotherapy. A thorough understanding of how ER stress affects antitumor immunity, as well as how to improve cancer immunotherapy by modulating ER stress is critical for translating these findings into clinical use.
Adjuvant recombinant human endostatin combined with toripalimab (anti-PD-1) in locally advanced melanoma: an exploratory phase 2 clinical trial incorporating single-cell RNA/TCR/BCR sequencing.
Hu X, Xu Y, Wang Z … +14 more , Yang L, Zheng B, Sun F, Liu D, Shi B, Zheng H, Liu X, Yu L, Zhang S, Yan Y, Yan W, Sun Y, Chen Y, Wang C
Mol Cancer · 2026 Apr · PMID 42046135 · Full text
PURPOSE: In East Asia, melanoma mainly presents as the acral lentiginous subtype, followed by the cutaneous subtype. Patients with completely resected stage III or IV melanoma in East Asia are at a high risk of disease r...
PURPOSE: In East Asia, melanoma mainly presents as the acral lentiginous subtype, followed by the cutaneous subtype. Patients with completely resected stage III or IV melanoma in East Asia are at a high risk of disease recurrence. The adjuvant efficacy of PD-1 inhibitors as monotherapy remains limited in this patient population, underscoring the need for combination strategies. PATIENTS AND METHODS: This prospective, single-arm, phase II trial (NCT05907512) aimed to investigate adjuvant recombinant human endostatin (rh-endostatin, an angiogenesis inhibitor) combined with toripalimab (a PD-1 inhibitor) in Chinese patients with resectable stage III to oligometastatic stage IV melanoma. The primary endpoint was 1-year relapse-free survival (RFS). Paired peripheral blood samples before and after the combined adjuvant therapy were collected for single-cell RNA sequencing, TCR/BCR sequencing, and biomarker identification. Two independent real-world cohorts of patients with locally advanced melanoma were assessed to validate the biomarkers. RESULTS: Forty-three eligible patients with resected stage III melanoma were prospectively enrolled. No patients with resected oligometastatic stage IV disease were enrolled. The 1-year RFS of the patients was 74.4%, with a median RFS of 27 months (95% confidence interval: 19, not reached). Anemia (12/43, 27.9%), elevated liver enzymes (11/43, 25.6%), and thyroid dysfunction (9/43, 20.9%) were the three most common treatment-related adverse events. The combined adjuvant therapy expanded the patients’ peripheral total T and NK cells, increased circulating CD8+ Tem and Teff cells and their TCR clonal diversities, improved the antigen-presenting capacity of B cells, elevated BCR clonal diversity, and raised the number of non-classical monocytes and their antigen-presenting capacity. The neutrophil-to-lymphocyte ratio and circulating CD8+ Tem cells were supported as candidate biomarkers associated with outcomes in the independent real-world cohorts. CONCLUSIONS: Adjuvant rh-endostatin combined with toripalimab shows encouraging clinical activity and may be associated with a potential survival benefit in Chinese patients with resected locally advanced melanoma. Adverse reactions were manageable. The increased quantities and functional changes of peripheral T cells, NK cells, B cells, and monocyte subsets provide mechanistic insights for the optimization of immunotherapy.
Metabolic reprogramming and molecular crosstalk at the cancer-endothelial interface in ovarian carcinoma.
Sousa B, Chiavassa A, Delgado L … +3 more , Gomes R, Mendes C, Serpa J
Mol Cancer · 2026 Apr · PMID 42045908 · Full text
Ovarian carcinoma (OC) is the most lethal gynecological malignancy, with high mortality due to late-stage diagnosis and the development of chemoresistance. Tumor progression relies on a complex interplay between cancer c...
Ovarian carcinoma (OC) is the most lethal gynecological malignancy, with high mortality due to late-stage diagnosis and the development of chemoresistance. Tumor progression relies on a complex interplay between cancer cells and the tumor microenvironment (TME), particularly endothelial cells (ECs), which support angiogenesis, nutrient supply, and metastasis. Aberrant neovascularization, driven primarily by VEGF signaling and hypoxia-inducible factors (HIFs), establishes a structurally and functionally abnormal vasculature that enhances tumor growth and dissemination. In the TME, ECs and OC cells undergo metabolic reprogramming, with glycolysis, fatty acid oxidation (FAO), and amino acid metabolism supporting angiogenesis, proliferation, redox balance, and chemoresistance. The bidirectional nutrient exchange establishes a metabolic symbiosis sustaining angiogenesis stimulation, tumor growth and survival under hypoxia and a pro-oxidative TME. Ultrastructural adaptations, including tunneling nanotubes (TNTs), facilitate direct cytoplasmic and organelle exchange, enhancing mitochondrial transfer, metabolic support, and therapy resistance. The formation of EC TNTs is regulated by stress-responsive pathways, including HIF-1α, VEGF, and Nrf2, which integrate hypoxia, oxidative stress, and metabolic signaling to reinforce vascular remodeling. This intricate network of signaling and metabolic interactions establishes a self-sustaining vascular niche that drives tumor aggressiveness and limits therapeutic efficacy. Understanding these mechanisms provides insight into potential therapeutic interventions, aiming to disrupt the cooperative tumor-EC network and overcome chemoresistance in OC.
Breast cancer immunotherapy: mechanisms of immune evasion, biomarkers, and emerging therapeutic strategies.
Shichkin VP, Morva A, Ulaganathan VK … +4 more , Erin N, Nativi C, Brezar SK, Rani S
Mol Cancer · 2026 Apr · PMID 42035063 · Full text
Breast cancer remains the most prevalent malignancy worldwide and a major cause of cancer-related mortality, representing a heterogeneous and therapeutically challenging disease. Although immunotherapy has revolutionized...
Breast cancer remains the most prevalent malignancy worldwide and a major cause of cancer-related mortality, representing a heterogeneous and therapeutically challenging disease. Although immunotherapy has revolutionized the treatment of several malignancies, its efficacy in breast cancer is constrained by tumor heterogeneity, low immunogenicity, particularly in hormone receptor (HR)-positive subtypes, and diverse immune evasion mechanisms. This review provides a comprehensive overview of current advances in understanding key mechanisms of breast tumor immune evasion and their overcoming by modern immunotherapy approaches, including immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell therapies, emphasizing biomarker-guided patient selection. We examine the roles of tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), antigen presentation, and programmed death-ligand 1 (PD-L1) expression in the tumor immune evasion and predicting response to immunotherapy. Our main focus is also on emerging strategies, including neoantigen- and DNA/RNA-based vaccines, chimeric and engineered antigen receptors, bispecific T-cell engagers, oncolytic viruses, and targeted immunotherapeutic approaches, which are promising tools for overcoming immune resistance. Furthermore, we evaluate rational combinations of immunotherapy with chemotherapy, radiotherapy, and targeted agents, added by immunosorption as an essential detoxification approach. Finally, we explore future directions emphasizing personalized, multimodal immunotherapy guided by multiomics and spatial profiling, integrated with artificial intelligence. Finally, we synthesize a framework for advancing immunotherapy in breast cancer and identify key areas requiring further translational and clinical investigation.
The RNA methylation modification as an immunometabolic regulatory hub in pancreatic cancer: from mechanistic insights to clinical translation perspectives.
Zhu Y, Ma K, Hao Q … +7 more , Fu K, Hei F, Sun N, Yin Z, Guo W, Zou H, Tan Z
Mol Cancer · 2026 Apr · PMID 42021253 · Full text
RNA methylation represents the most abundant post-transcriptional modification in RNA and has recently emerged as a central topic in molecular biology. It precisely regulates various biological functions by influencing k...
RNA methylation represents the most abundant post-transcriptional modification in RNA and has recently emerged as a central topic in molecular biology. It precisely regulates various biological functions by influencing key processes like RNA splicing, translation, transport, and stability. Pancreatic cancer remains one of the most aggressive and lethal malignancies, with its high mortality largely attributed to late diagnosis and limited therapeutic options. Recent research has shown that RNA methylation is intimately linked to tumor immunity and is vital in forming the tumor microenvironment (TME). Moreover, accumulating evidence indicates that reprogrammed metabolism is a critical driver of pancreatic tumorigenesis, progression, therapeutic response, and prognosis. RNA methylation, particularly N6-methyladenosine (m⁶A), regulates RNA translation and stability through the coordinated actions of methyltransferases (“writers”), demethylases (“erasers”), and binding proteins (“readers”), ultimately shaping immune and metabolic pathways in pancreatic cancer. By reprogramming tumor immunity and metabolism, RNA methylation critically governs key malignant behaviors such as cell proliferation, invasion, and metastasis. This review provides a comprehensive overview of the molecular mechanisms and biological functions of RNA methylation, emphasizing its dual roles in immune modulation and metabolic reprogramming in pancreatic cancer. Furthermore, we explore the intricate crosstalk between immune responses and metabolic networks mediated by m⁶A modifications. By integrating current advances, this review aims to establish a conceptual framework for understanding the immunometabolic regulation of pancreatic cancer and to highlight potential therapeutic strategies targeting RNA methylation for improved non-surgical treatment outcomes.
Genetically driven immune microenvironment states associate with therapeutic responses in MYD88 mutant lymphomas.
Celay J, Recalde M, Revuelta MV … +36 more , Larrayoz M, Vicente C, Lozano T, Gil C, Chapman JR, Garcia-Lacarte M, Gonzalez C, Ariceta B, Rodriguez S, Lasa M, Garcia-Barchino MJ, Fresquet V, Jimenez M, Sanz S, Du MQ, Roncador G, Vega Z, Sacco A, Roccaro A, Knittel G, Reinhardt HC, Piazza R, Herter S, Goodhew R, Caron J, Roos-Weil D, Miguel JS, Canales M, Hodson DJ, Lossos IS, Lasarte JJ, Roa S, Prosper F, Paiva B, Cerchietti L, Martinez-Climent JA
Mol Cancer · 2026 Apr · PMID 42010569 · Full text
The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain largely unexplored. Here, we utilized murine models with oncogenically...
The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain largely unexplored. Here, we utilized murine models with oncogenically active MYD88 and additional genetic lesions co-triggered at selected B cell stages to generate human-like lymphomas harboring the MYD88L265P mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL). Genetically diverse lymphoma cells employ distinct immune evasion mechanisms that shape unique lymphoma microenvironment (LME) states. In this setting, clonally expanded T-cells function as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, the efficacy of standard-of-care and novel immunotherapies was determined using individual T-cell features. Furthermore, the experimental targeting of newly identified immune mechanisms has improved therapeutic responses in vivo. Our results elucidate that genetically driven LME landscapes influence therapeutic outcomes across distinct lymphoma subtypes, providing proof-of-concept for personalized treatment based on immune LME information.
MTSS1-dependent ubiquitin modifications mediated by FBXO44 remodel the actin cytoskeleton to promote gastric cancer progression.
Pan G, Xu Q, Yuan L … +14 more , Wang L, Zhang C, Le J, Zhao J, Zhang K, Hu X, Liang H, Chen X, Dong J, Guan X, Tao F, Miao K, Chen ZS, Qin JJ
Mol Cancer · 2026 Apr · PMID 41998764 · Full text
Dynamic cytoskeletal homeostasis drives malignant transformation in tumor cells and represents a therapeutic vulnerability. Therapeutic targeting of this equilibrium may improve outcomes for cancer patients. Rac1 acts as...
Dynamic cytoskeletal homeostasis drives malignant transformation in tumor cells and represents a therapeutic vulnerability. Therapeutic targeting of this equilibrium may improve outcomes for cancer patients. Rac1 acts as a central molecular switch that controls actin cytoskeleton dynamics. Although multiple biological strategies modulate its spatiotemporal activity to maintain actin cytoskeleton homeostasis, the underlying molecular mechanisms remain unclear. Here, we identify FBXO44 as a critical regulator of Rac1 nucleocytoplasmic trafficking via its interaction with MTSS1. In gastric cancer (GC), FBXO44 directs two distinct ubiquitination programs on MTSS1: K63-linked polyubiquitination of MTSS1 promotes Rac1 nuclear translocation, whereas K11-linked polyubiquitination induces proteasomal degradation of MTSS1, restricting Rac1 nuclear entry. This ubiquitin-mediated coordination reprograms nucleocytoplasmic Rac1 signaling distribution and remodels the actin cytoskeleton. Structural analysis demonstrates that FBXO44 binds MTSS1 via distinct domains, dynamically balancing these opposing ubiquitination events by controlling MTSS1 abundance, thereby fine-tuning actin cytoskeletal dynamics. Clinically, this regulatory axis supports an oncogenic phenotype: FBXO44 overexpression correlates with enhanced Rac1 signaling and activation of associated pathways in advanced GC. Importantly, the expression balance of the FBXO44/MTSS1 axis significantly influences patient prognosis. Our findings provide mechanistic insights into cytoskeletal regulation and establish a translational framework for GC therapy.
The evolving role of OMICS in gastrointestinal tumor biology and clinical practice.
Li Q, Zhang J, Chen J … +6 more , Zhang Q, Liu R, Zhu J, Qing Y, Wei X, Sheng J
Mol Cancer · 2026 Apr · PMID 41992238 · Full text
Due to late diagnosis, high molecular diversity, and limited response to therapeutic intervention, gastrointestinal (GI) cancers result in a considerable number of cancer-related deaths. Classic clinicopathological class...
Due to late diagnosis, high molecular diversity, and limited response to therapeutic intervention, gastrointestinal (GI) cancers result in a considerable number of cancer-related deaths. Classic clinicopathological classification and single omics analysis fail to adequately convey the extensive biological complexity related to progression of disease, developed therapy resistance and recurrence of the disease. As a result, the recent introduction of integrated multi-omics including genomics, epigenomics, transcriptomics, proteomics, metabolomics and spatial profiling as well as the emerging use of liquid biopsy is substantially reshaping our understanding of and clinical approach to GI cancers. This review summarizes developments to illustrate how the incorporation of multi-omics across GI tumors offers a better understanding of GI cancers and providing more precise and less costly ways to detect disease earlier, develop molecular subtypes of the tumors with greater accuracy for the purpose of developing an individualized risk stratification system for patients. Furthermore, the article will discuss the growing use of minimal residual disease monitoring and the use of ctDNA in guiding a patient's post-operative surveillance and treatment decision-making process. In addition, this review focuses on the value of using multi-omics-based knowledge of a tumor's microenvironment to better predict how effective immunotherapy will be and support the effective combination of drugs for the treatment of GI cancers and how targeted therapy will broaden the clinical practice landscape for developing therapeutics containing new vulnerable targets. Finally, the review provides an overview of current barriers to the implementation of multi-omics and point out to future opportunities. Collectively, emerging omics data suggest a meaningful shift toward precision oncology in gastrointestinal cancers, though widespread clinical implementation remains an active area of investigation.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe