It has been five years since the last version of the clinical practice guidelines for the management of adult diffuse gliomas was published by the Asian Glioma Genome Atlas (AGGA). Significant progress and revisions have occurred in the diagnosis and treatment of adult diffuse gliomas in recent years. In response to these updates, the joint guideline committee of the Chinese Glioma Cooperative Group (CGCG), the Society for Neuro-Oncology of China (SNO-China), and the Chinese Brain Cancer Association (CBCA) has revised the clinical practice guidelines. This updated guideline emphasizes molecular and pathological diagnostics, as well as the primary treatment modalities of surgery, radiotherapy, chemotherapy, and targeted therapy. Additionally, we have incorporated findings from recent clinical trials of new therapies to align with cutting-edge treatment strategies. This guideline is designed to serve as a practical resource for all professionals involved in managing adult diffuse glioma patients, while also providing valuable information for insurance companies and other institutions responsible for regulating cancer care costs in China and beyond.

Kirsten rat sarcoma (KRAS) mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The development of allele-specific KRAS inhibitors, especially those targeting the KRAS variant, represents a landmark achievement in precision oncology. Yet their therapeutic benefit is often transient, as tumors rapidly develop seemingly heterogeneous resistance mechanisms. Increasing evidence implicates SRC, a non-receptor tyrosine kinase frequently hyperactivated in KRAS-mutant cancers, as a central regulator of resistance. This review integrates current evidence supporting SRC's role in mediating diverse resistance pathways, including mitogen-activated protein kinase (MAPK) reactivation, transcriptional/epigenetic reprogramming, metabolic adaptation, multidrug resistance, cell death evasion, and remodeling of the tumor microenvironment. We also critically examine the shortcomings of early-generation SRC inhibitors in solid tumors and highlight emerging therapeutic avenues such as next-generation inhibitors, proteolysis-targeting chimera (PROTAC) degraders, and biomarker-guided combination strategies. By connecting molecular insights with preclinical and clinical findings, this review positions SRC as a therapeutically actionable vulnerability in KRAS-driven cancers and outlines a translational framework for overcoming drug resistance.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by high recurrence rates and limited treatments beyond chemotherapy. The interplay between tumor cells and the tumor microenvironment plays a critical role in TNBC progression, with copper homeostasis emerging as a key regulator of this dynamic niche. Our previous study indicated elevated serum copper as a predictor of poor prognosis for TNBC patients, but its specific role and underlying mechanisms remains to be elucidated. Herein, notable upregulation of STEAP3 was found in high-copper TNBC patients and significantly associated with poor prognosis. The intracellular copper level markedly increased upon STEAP3 overexpression and decreased following STEAP3 knockdown. Through comprehensive in vitro and in vivo experiments, we proved that copper facilitated cell proliferation, migration, xenograft tumor growth and lung metastasis, which were inhibited by copper chelator tetrathiomolybdate. Mechanistically, copper directly bound to CDK16 kinase, leading to its activation, in turn enhanced CDK16 binding and subsequently activating JAK1 kinase to upregulate transcription of c-Myc and cyclin D1. Critically, targeted knockdown of STEAP3 remarkably inhibited TNBC cells proliferation, migration and xenograft tumor growth. These findings unveil a critical pro-tumorigenic copper-driven pathway-distinct from cuproptosis-operating through STEAP3/copper/CDK16/JAK1 axis, and highlight STEAP3 as a promising therapeutic target for TNBC.

Epithelial ovarian carcinoma, the deadliest gynecological malignancy, frequently develops treatment resistance through polyploid giant cancer cells (PGCCs) that typically emerge after carboplatin-paclitaxel chemotherapy. Accumulating evidence suggests that PGCCs exhibit traits similar to those of cancer stem cells (CSCs), including expression of stemness markers, self-renewal, and resistance to treatment. Although Wnt/β-catenin signaling is a major driver of stemness and chemoresistance in ovarian carcinoma, the specific mechanisms by which it activates cancer stemness of PGCCs remain unclear. This study investigates the role of SIRT1-mediated deacetylation of β-catenin in PGCC stemness, with a specific focus on SIRT1's subcellular localization. Immunohistochemical analysis of ovarian carcinoma samples from patients receiving neoadjuvant chemotherapy revealed that nuclear β-catenin staining in PGCCs correlated with SOX2-positive expression. Comparative proteomics further demonstrated the enrichment of differentially expressed proteins related to the Wnt pathway and stem cell programs in PGCCs compared to diploid tumor cells, highlighting the role of the Wnt/β-catenin pathway in the cancer stemness of PGCCs. Critically, PGCCs with overexpressed cytoplasmic SIRT1 (SIRT1) showed increased CSC marker expression, chemoresistance, colony and spheroid formation abilities, and hyperactivation of the Wnt/β-catenin pathway, compared to PGCCs overexpressing the nuclear-predominant wild-type SIRT1 (SIRT1). Mechanistically, cytoplasmic retention of SIRT1 in PGCCs stabilizes β-catenin, facilitates its nuclear accumulation, and decreases its deacetylation of nuclear β-catenin through post-translational modification. Our findings establish that the cytoplasmic SIRT1/β-catenin axis contributes to PGCC stemness, elucidating a novel mechanism underlying chemoresistance. Therefore, targeting cytoplasmic SIRT1 represents a promising therapeutic strategy to overcome PGCC-mediated resistance in this lethal carcinoma.

As a novel targeted therapeutic approach, peptide-drug conjugates (PDCs) integrate peptides, drug payloads, and linkers to establish an efficient drug delivery system. In addition to retaining the selective advantage inherent in targeted therapy, this modular approach confers a spectrum of therapeutic capabilities, such as enhanced drug targeting, controlled drug release, improved bioavailability, and reduced systemic toxicity and immunogenicity. Moreover, by leveraging their active tumor-targeting capacity and stimulus-responsive drug release properties, PDCs could induce immunogenic cell death and synergistically reprogram the immunosuppressive tumor microenvironment, thereby enabling precise intervention in tumors. This strategy exhibits a favorable efficacy-to-toxicity profile and remarkable potential in immunotherapy, ultimately leading to an improved therapeutic index against tumors. Currently, the PDC Lutathera has been approved by the U.S. FDA for the treatment of cancer, and several other PDCs candidates are currently under investigation in clinical trials. This review provides a systematic summary of the recent research progress in PDCs for cancer treatment over the past five years, focusing on the molecular design strategies based on peptides, linkers, and drugs, as well as recent technological breakthroughs, such as PDCs constructed using nano-strategies, and the applications of PDCs in monotherapy and combination therapy. Additionally, the therapeutic advantages, existing challenges and future clinical applications of PDCs are also discussed. This review tries to offer critical insights into PDCs and provides new perspectives for the future development of antitumor therapies.

Necroptosis, a form of immunogenic cell death (ICD), is frequently impaired in cancer due to the silencing of key regulators, such as RIP3. Despite its potential immunogenic benefits, restoring necroptosis in cancer therapy has been largely underexplored, primarily due to the lack of effective strategies or agents that specifically engage necroptosis without activating apoptosis. In this study, we investigated strategies to restore necroptosis for chemosensitization in RIP3-silenced colorectal cancer (CRC) cells. While reconstituting RIP3 did not impact cell killing by chemotherapy, bypassing RIP3 to induce necroptosis using the natural compound OSW-1 emerged as a promising strategy. OSW-1 displayed strong synergy with 5-fluorouracil (5-FU), effectively eliminating RIP3-silenced CRC cells and tumors through the induction of both necroptosis and apoptosis. Cell death triggered by the OSW-1/5-FU combination was mediated by p53 and CaMKIIδ-driven MLKL phosphorylation, a critical step in the execution of necroptosis. The combination robustly induced ICD hallmarks in CRC cells and immune infiltration in syngeneic tumors. The in vivo antitumor effect of the OSW-1/5-FU combination was largely dependent on antitumor immunity, and abolished by anti-CD8 antibody or immunodeficient hosts. Furthermore, the combination increased immune infiltration in patient-derived primary CRC Air-Liquid Interface (ALI) organoid cultures with autologous immune tumor microenvironment. Collectively, our findings support a novel strategy to activate RIP3-independent necroptosis, providing a compelling rationale to boost the efficacy of chemotherapy via enhanced CRC cell killing and antitumor immunity.

Pancreatic ductal adenocarcinoma (PDAC) has an exceptionally poor prognosis. Most genomic studies conducted to discover potential targets to improve PDAC prognosis have been constrained by biased cohort compositions and limited clinical information. Therefore, we aimed to develop a large-scale, unbiased, and well-organized PDAC genomic dataset. Primary pancreatic tissue samples were exclusively obtained from patients with PDAC using endoscopic ultrasound-guided fine-needle biopsy, and whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were conducted. Subsequently, comprehensive clinico-genomic analysis was performed by integrating this genomic dataset with detailed clinical information. A unique and unbiased genomic dataset, comprising 205 WES and 93 WTS datasets from 237 Asian patients with PDAC, was developed. The clinico-genomic analysis revealed distinct genetic features associated with various clinical phenotypes. Specifically, patients with liver metastasis exhibited a high frequency of TP53 mutation, increased chromosomal instability, and high frequency of copy number variants as well as KRAS allelic imbalance. Additionally, potential biomarkers derived from broad genomic data, including tumor mutation burden, mutation signatures, scar-based homologous recombination deficiency signatures, and RNA subtypes, were validated for their clinical utility. This large-scale, unbiased genomic dataset addresses the limitations of previous genomic studies in PDAC, facilitating comprehensive clinico-genomic analyses with significant clinical utility.

The function of circular RNAs (circRNAs) located within the mitochondria in the pathogenesis of urothelial carcinoma of the bladder (UCB) remains largely unexplored. This study identified a mitochondria-located circRNA named circRCP from the nuclear genome of UCB cells. It is frequently upregulated in UCB and serves as an independent prognostic factor. This study further illustrates that circRCP enhances UCB tumorigenesis by regulating intracellular redox homeostasis. The knockdown of circRCP heightens mitochondrial oxidative stress, which leads to ROS generation, consequently triggering UCB cell apoptosis. Mechanistically, by forming a circRCP/LRPPRC/SLIRP RNA-protein ternary complex, circRCP enhances the LRPPRC/SLIRP stability and protects LRPPRC from ubiquitination and proteasomal degradation. Clinically, UCBs exhibiting high circRCP and LRPPRC expression had the worst outcomes. Taken together, we have identified a mitochondria-located circRNA that protects UCB cells from oxidative stress, highlighting its potential role in UCB pathogenesis and warranting further investigation into its therapeutic applicability.

Small cell lung cancer (SCLC) is a lethal lung malignancy, which is associated with distant metastasis and chemoresistance. Due to the limited availability of targeted therapies, identifying a potential therapeutic target is a pressing unmet need in SCLC. Single-cell and bulk-transcriptomic datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression was observed in human and murine SCLC tissues and cell lines. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1; TP53 ; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8 T cells, and T cell-mediated killing of SCLC cells. Additionally, FOXM1 inhibition enhanced CD8 T cell and macrophage recruitment in the tumor microenvironment (TME) of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.

Polyploid giant cancer cells (PGCCs) are a unique subtype of cancer cells, characterized by distinct morphological features and a strong association with therapeutic resistance and cancer progression. Targeting PGCCs could provide novel therapeutic strategies and improve patient prognosis. However, the mechanisms underlying PGCC formation remain poorly understood, and effective therapeutic targets have not yet been fully identified. Here, we investigated the role of chromatin licensing and DNA replication factor 1 (CDT1), a vital DNA replication licensing factor, in PGCC formation. Our findings revealed that high CDT1 expression in tumors correlated with PGCC formation and poor prognosis. CDT1 overexpression significantly induced PGCC formation, enhanced cancer stemness, and promoted chromosomal instability. Interestingly, PGCCs induced by CDT1 overexpression exhibited abnormal centrosome numbers, raising questions about the role of CDT1 in centrosome duplication. We found CDT1 localized to the centrosome through its centrosomal localization signal and facilitated centrosome amplification. Notably, inhibition of the PLK4/SASS6 axis using siRNA, the selective PLK4 kinase inhibitor Centrinone, or a kinase-dead PLK4 mutant markedly suppressed centrosome amplification and PGCC formation induced by CDT1 overexpression. Moreover, we identified simvastatin as a potent inhibitor of CDT1, effectively inhibiting CDT1-mediated centrosome amplification and PGCC formation. In summary, our findings reveal a critical role for CDT1 in driving centrosome amplification and PGCC formation through activation of the PLK4/SASS6 axis, which subsequently contributes to therapeutic resistance and malignant progression.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer (PCa) that often emerges in response to androgen receptor pathway inhibitors (ARPIs), which are widely used in treating metastatic castration-resistant and hormone-sensitive prostate cancer. The incidence of NEPC is increasing, yet effective therapeutic strategies remain limited due to an incomplete understanding of its molecular drivers. Through transcriptomic analyses of human prostate tumor samples, we identified the histone lysine demethylase KDM4A as uniquely overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Functional validation demonstrated that KDM4A is a key regulator of NEPC progression and a promising therapeutic target, as knockdown or knockout of KDM4A suppresses NEPC cell proliferation in vitro and tumor growth in vivo. Mechanistically, we found that KDM4A directly regulates the transcription of the oncogene MYC, which we show is essential for NEPC cell growth through knockdown and inhibitor studies. Importantly, pharmacologic inhibition of KDM4A using QC6352, a potent pan-KDM4 inhibitor, significantly reduced NEPC cell proliferation in vitro and tumor growth in vivo, providing proof-of-concept for therapeutic targeting. Collectively, our findings establish KDM4A as a critical epigenetic driver of NEPC through MYC regulation and demonstrate its therapeutic potential for this lethal disease that currently lacks effective treatments.

Prostate cancer (PCa) remains one of the most prevalent malignancies among men, with radiotherapy (RT) serving as a cornerstone of treatment. However, radioresistance (RR) remains a major clinical challenge, contributing to treatment failure, disease recurrence, and poor prognosis. A major driver of RR is the enhanced DNA damage repair (DDR) ability of PCa cells, which allows them to evade RT-induced cell death. This review critically examines the molecular basis of RR in PCa, with particular focus on DDR pathways. We address the role of key genetic alterations, including mutations in BRCA2, ATM, and PARP1, on RT response, highlighting their potential as therapeutic targets to overcome RR. We further explore the interplay of DDR inhibition with androgen receptor (AR) signaling and its ability to potentiate antitumor immunity through activation of the cGAS-STING pathway, type I interferon production, and regulation of immune checkpoints. By leveraging insights into DDR mechanisms and therapeutic opportunities, this review provides a comprehensive perspective to enhance RT efficacy and improve clinical outcomes in PCa patients.

Polyploid giant cancer cells (PGCCs), characterised by multinucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and genomic consequences remain underexplored. In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting that they arise de novo rather than through clonal expansion. scDNA-seq revealed that PGCCs originate from the dominant tumour population and exhibit extensive copy number heterogeneity, either due to subsequent or ongoing chromosomal instability. Both clonal and subclonal chromothripsis-like events were identified in PGCCs, indicating that chromothripsis is a key driver of heterogeneity in these cells and is linked to multinucleation rather than mononuclear PGCC formation. FACS-based ploidy analysis of one undifferentiated pleomorphic sarcoma (UPS) revealed a twice whole-genome-duplicated population (6.2n) distinct from the bulk tumour (3.3n). This population contained all clonal, but none of the subclonal chromothripsis-like events observed in PGCCs. Our findings highlight PGCCs as a highly heterogeneous and evolutionarily dynamic component of UPSs. The recurrent chromothripsis-like events observed in PGCCs suggest ongoing genomic reshaping that may drive tumour progression and the poor clinical outcomes observed for these tumours.

Use of immune checkpoint inhibitors (ICIs) has significantly improved patients' survival with especially lung cancer. However, immunotherapy-related adverse events (irAEs) frequently occur and negatively impact patients' quality of life. While investigations into genetic predictors of irAEs remain ongoing, no robust genetic loci predictive of these toxicities have been definitively established to date. To investigate the pharmacogenomic markers related to irAEs of PD-1/PD-L1 inhibitors in lung cancer patients, we collected blood specimens from 1,467 patients. After rigorous screening and quality control procedures, 785 of these patients were enrolled in a two-stage genome-wide association study (GWAS). The study comprised an initial discovery phase, in which 455 patients underwent microarray-based analysis, and a subsequent validation phase with an independent cohort of 330 patients. Of 688,783 SNPs genotyped using whole genome-wide microarray screening, 52 SNPs were validated using MassARRAY system. The potential impact of significant variants investigated by eQTL analysis. We identified three novel SNPs that are significantly associated with irAEs of PD-1/PD-L1 inhibitor treatments in these lung cancer patients in both discovery and validation cohorts, rs192921786 (discovery: P = 4.09 × 10, OR = 9.57; validation: P = 0.043, OR = 4.42) for pneumonitis, rs2498632 (discovery: P = 1.85 × 10, OR = 0.50; validation: P = 0.021, OR = 0.65) for anemia and rs17080141 (discovery: P = 9.11 × 10, OR = 3.16; validation: P = 0.027, OR = 1.86) for thrombocytopenia. Lung cancer patients with rs192921786 T allele, rs2498632 C allele, and rs17080141 A allele were more likely to suffer immunotherapy related pneumonitis, anemia and thrombocytopenia, respectively. In conclusion, rs192921786, rs2498632 and rs17080141 are novel candidate risk loci for pneumonitis, anemia, and thrombocytopenia in lung cancer patients receiving immunotherapy. These findings warrant further investigation and validation to assess their potential as predictive biomarkers.

Immune checkpoint blockade (ICB) therapies targeting the programmed cell death 1 (PD-1)/ PD-1 ligand 1 (PD-L1) axis provide significant clinical benefits across multiple tumor types. Although interferon (IFN)-γ is essential for anti-tumor immunity, sustained IFN-γ signaling in the tumor microenvironment potently upregulates PD-L1 expression in tumor cells and induces profound T cell exhaustion, limiting the efficacy of ICB therapies. Therefore, further investigation into the regulation of IFN-γ-PD-L1 signaling is necessary for the development of more effective therapeutic strategies. Herein, transmembrane protein 199 (TMEM199) is identified as a novel regulator of IFN-γ-driven PD-L1 transcription. Mechanistically, TMEM199 and its important partner coiled-coil domain containing 115 (CCDC115) interact with IFNGR1/2 and facilitate their trafficking to RAB11A-positive recycling endosomes. TMEM199/CCDC115 also recruits transport protein particle (TRAPP) Ⅱ to the recycling endosomes and activates RAB11A, leading to enhanced IFNGR1/2 recycling and downstream PD-L1 upregulation. Collectively, these findings reveal that TMEM199 might be a promising therapeutic target for immunotherapy.

Understanding the molecular mechanisms that drive melanoma metastasis within the tumor microenvironment remains a critical objective in cancer research and therapy development. Our study identifies IL-1 receptor-associated kinase M (IRAK-M) as a previously underappreciated regulator of melanoma progression. We found that IRAK-M is either absent or expressed at low levels in human melanomas, and its expression correlates positively with patient survival. To investigate its functional role, we performed RNA sequencing on melanoma cells with restored IRAK-M expression. This analysis revealed PTPN22, a tyrosine phosphatase, as a key downstream effector upregulated by IRAK-M. Notably, PTPN22 expression also correlated with improved clinical outcomes. Functional assays in vitro, in murine models, and in patient-derived samples demonstrated that restoring IRAK-M or PTPN22 expression significantly impaired melanoma cell adhesion, migration, and transendothelial invasion-key steps in metastasis. Mechanistically, IRAK-M induced PTPN22 to dephosphorylate migration-related proteins, including Src family kinases, and reduced matrix metalloproteinase (MMP) secretion and extracellular matrix (ECM) remodeling. Importantly, PTPN22 knockout abrogated the anti-migratory effects of IRAK-M, confirming its essential role in this pathway. These findings establish the IRAK-M-PTPN22 axis as a critical suppressor of melanoma metastasis within the tumor microenvironment and highlight its potential as a therapeutic target to limit tumor dissemination and improve patient outcomes.

Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, characterized by high mortality, recurrence, and metastasis. Despite advancements in therapies such as surgery, targeted treatment and immunotherapy, therapeutic resistance and immune evasion remain significant challenges. In our study, we integrated multi-omics data, including spatial transcriptomics, single-cell RNA sequencing, H3K18la ChIP-seq, CRISPR data and bulk transcriptomics, to explore the metabolic heterogeneity of LUAD, particularly focusing on glycolysis and histone H3K18 lactylation (H3K18la). Our findings revealed significant intra- and inter-tumoral metabolic heterogeneities, with glycolysis and H3K18la-related genes being more active in tumor regions. We also identified H3K18la-related gene activities as a marker of LUAD progression, demonstrating its strong correlation with glycolysis and tumor cell phenotypes. Based on these insights, we developed a machine learning-based prognostic model (termed as "Kla.Sig") that predicts patient survival and immunotherapy response, with validation across multiple cohorts. The model highlighted the immunosuppressive tumor microenvironment in high-risk score patients, with lower immune cell infiltration and higher immune evasion ability. In addition, we developed an online R shiny application "LUAD-Kla.Sig" to facilitate users' estimation of survival based on Kla.Sig model. In-silico drug screening suggests that targeting Polo-like kinase 1 (PLK1) with BI-2536 could be an effective strategy for high-risk LUAD patients. This study offers a deeper understanding of LUAD metabolism and immune evasion at single-cell and spatial resolution, proposing potential therapeutic targets and a risk-stratified treatment strategy for precision medicine.