Retroperitoneal sarcoma (RPS) is a type of malignant tumour arising from mesenchymal tissues within the retroperitoneal space. RPSs tend to develop covertly and are often undiscovered when they have already grown significantly and invaded surrounding tissues and organs. These malignancies demonstrate high recurrence rates, present surgical challenges and exhibit limited responsiveness to radiotherapy and chemotherapy. Serum-derived molecules are known to play critical roles in tumourigenesis and tumour progression. However, the serum molecular profile of RPS patients remains unclear.

We performed multi-omics analysis of serum samples from patients with retroperitoneal dedifferentiated liposarcoma. Prolactin concentrations were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). RNA-seq facilitated the identification of candidate signalling pathways, while gene expression was validated through quantitative polymerase chain reaction, immunohistochemistry and western blot analyses. Molecular mechanisms underlying transcriptional regulation were investigated through Chromatin Immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter gene assays.

Integrative multi-omics profiling identified significant perturbations in galactose metabolism coupled with marked elevation of prolactin (PRL) levels in Retroperitoneal Liposarcoma (RLPS) patients. Further screening of serum prolactin levels in 100 patients with retroperitoneal tumours revealed that 90% of the cases exhibited hyperprolactinaemia in our research cohort, encompassing both malignant sarcomas and benign tumours. Studies at the clinical sample, cellular and animal levels have found that abnormally elevated prolactin in the serum can originate from sarcoma tissues. Mechanistic investigations identified SRY-box transcription factor 4 (SOX4) as a previously unrecognised transcriptional regulator of PRL. Functionally, PRL not only enhanced liposarcoma cell and fibrosarcoma cell proliferation but also conferred resistance to MDM2 inhibitors. Signalling pathway analysis revealed that PRL activates the Janus Kinase-Signal Transducer and Activator of Transcription Pathway (JAK-STAT) signalling pathway and up-regulates c-MYC expression.

This study indicates that PRL can serve as an oncogenic driver and therapeutic target. The identification of SOX4-PRL-c-MYC signalling axis provides actionable insights for developing novel therapeutic strategies against this malignancy.

Retroperitoneal sarcoma cells can secrete prolactin into the bloodstream, inducing hyperprolactinaemia, which subsequently triggers metabolic reprogramming, such as glucose metabolism. SOX4 can function as a transcription factor that facilitates PRL transcription. PRL can activate the JAK-STAT signalling pathway by binding to PRLR on sarcoma cells, leading to the up-regulation of c-MYC.

Dysregulation of transcription factors is a hallmark of lung tumorigenesis, and Sex-determining region Y-box 9 (SOX9) has emerged as a putative master regulator at the intersection of development and malignancy. Building on evidence from lung and other solid tumors, we summarize how aberrant SOX9 expression, shaped by epigenetic modification, post-translational regulation, and non-coding RNAs, drives proliferation, survival, invasion, and therapy resistance. In lung cancer, SOX9 appears to orchestrate a stem-like, plastic cell state, promoting epithelial-mesenchymal transition (EMT), metastatic dissemination, and remodeling of the tumor microenvironment (TME). These context-dependent functions position SOX9 both as an oncogenic driver and, in selected settings, as a modulator of treatment response. This review integrates current mechanistic and translational data to frame SOX9 as a clinically actionable node within key signaling circuits relevant to non-small cell and small cell lung cancer. We highlight emerging strategies that directly or indirectly target SOX9, including interference with upstream pathways, epigenetic reprogramming, and RNA-based approaches designed to modulate SOX9 expression or activity. Finally, we propose SOX9 as a dual biomarker and therapeutic handle to guide rational combination therapies aimed at overcoming drug resistance and improving patient stratification. By connecting molecular insight with unmet clinical needs, this article outlines a conceptual roadmap for SOX9-centered therapeutic approaches in lung cancer. A key novelty of this review is the integration of SOX9-centered molecular mechanisms with therapeutic resistance, biomarker potential, and emerging indirect targeting strategies in lung cancer, thereby providing a translational framework for future SOX9-guided interventions.

Accumulating evidence indicates that indirubin exerts inhibitory effects on prostate cancer (PCa) progression. However, the role and underlying mechanisms of indirubin in sensitizing PCa to docetaxel remain unclear. CCK-8 assays were initially used to determine the effect of indirubin on enhancing docetaxel sensitivity in PCa cells. Following this, the expression levels of circ-Vav3 were quantified using quantitative real-time PCR (RT-qPCR) to evaluate its potential role in docetaxel resistance. Functional experiments, including flow cytometry-based apoptosis analysis and Transwell migration/invasion assays, were conducted to assess the impact of circ-Vav3 modulation and indirubin treatment on cell viability and behavior in response to docetaxel. Rescue experiments were subsequently performed to further confirm the regulatory effect of indirubin on circ-Vav3. Additionally, xenograft tumor models in nude mice were utilized to evaluate the therapeutic efficacy of indirubin in vivo. Mechanistic interactions between circ-Vav3, miR-204-5p, and MAPK1 were further investigated using RNA pulldown assays, luciferase reporter assays, and Western blot analyses. Indirubin enhanced the sensitivity of PCa cells to docetaxel by downregulating the expression of circ-Vav3, which was found to be significantly upregulated in docetaxel-resistant PCa cells. Silencing circ-Vav3 effectively reversed this resistance, as evidenced by increased apoptosis, reduced cell migration and invasion, and decreased autophagic activity. Notably, indirubin treatment suppressed circ-Vav3 expression and thereby restored docetaxel sensitivity both in vitro and in xenograft tumor models. Mechanistically, circ-Vav3 acted as a competing endogenous RNA (ceRNA) by sponging miR-204-5p, which led to the upregulation of the autophagy-related kinase MAPK1. Inhibition of MAPK1 effectively suppressed autophagy and re-sensitized docetaxel-resistant PCa cells, further confirming the critical regulatory role of the circ-Vav3/miR-204-5p/MAPK1 signaling axis in mediating chemoresistance. Our findings demonstrate that circ-Vav3 promotes docetaxel resistance in PCa by sponging miR-204-5p and subsequently activating MAPK1-mediated autophagy. Indirubin effectively restores chemosensitivity by targeting this regulatory pathway, offering a promising therapeutic strategy for overcoming chemoresistance in castration-resistant prostate cancer (CRPC).

Antibody-drug conjugates (ADCs) have transformed the therapeutic landscape of solid tumors; however, responses remain heterogeneous and complex to predict. In addition, a growing number of multiple ADC targets are either approved or in late-stage clinical development, such as NECTIN-4, HER2, or TROP2 for metastatic urothelial cancer. Spatial multiomics-representing next-generation methods that couple high-plex RNA sequencing and multiplex protein imaging with precise x-y-z coordinates within tissues-offer a direct way to correlate (ADC) antigen expression, cell state information, and micro-anatomical context with patient treatment outcomes. In this review, we highlight suitability and technological advancements in current spatial transcriptomics and proteomics approaches to decode modes of action and resistance to ADCs and extract biological insights, particularly in metastatic urothelial cancer-and propose an integrative framework that combines spatial readouts with machine and/or deep learning-driven analytics to stratify patients, forecast on- and off-target toxicities, and guide next-generation linker-payload designs or combination therapies.

BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with limited prognostic biomarkers and therapeutic targets. This study aims to develop a robust protein-based prognostic model and investigate the functional role of RAPTOR in HNSCC progression. MATERIAL AND METHODS Proteomic data from The Cancer Proteome Atlas and transcriptomic data from The Cancer Genome Atlas were integrated to identify prognosis-related proteins, and a multivariable Cox regression model was developed. Functional studies, including lentiviral knockdown, proliferation and invasion assays, RNA sequencing, and xenograft models, were conducted to evaluate the role of RAPTOR (encoded by the RPTOR gene). Since RAPTOR is an essential component of mTORC1 and lacks a direct inhibitor, the mTORC1 inhibitor rapamycin was used as a pharmacological surrogate to assess the therapeutic potential of targeting RAPTOR-mediated signaling. RESULTS A 7-protein prognostic model (CD45, RAPTOR, SETD2, MERIT40_pS29, HER3_pY1289, Hexokinase-I, and BETACATENIN) stratified patients into high- and low-risk groups with significantly different overall survival, and the risk score remained an independent prognostic factor. RAPTOR was markedly upregulated in HNSCC and correlated with immune infiltration. Functional assays revealed that RAPTOR silencing inhibited proliferation, migration, and invasion, suppressed PI3K/AKT/mTOR signaling and uPA expression, and upregulated both S100A8/A9 levels. Rapamycin treatment recapitulated these effects in vitro and in vivo. CONCLUSIONS This study identifies a novel protein-based prognostic model for HNSCC and demonstrates that RAPTOR promotes tumor progression through mTOR signaling and S100A8/A9-uPA regulation. Targeting RAPTOR-mediated pathways may offer new strategies for precision therapy in HNSCC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Cyclin-dependent kinase 4 (CDK4) is a well-validated oncogenic driver in NSCLC, yet current CDK4 inhibitors-predominantly based on the aminopyrimidine scaffold-are limited by structural homogeneity and the rapid emergence of acquired resistance, underscoring the need for novel chemotypes.

We employed a HuProt human proteome microarray to screen for direct cellular targets of artesunate, an FDA-approved artemisinin derivative. Candidate interactions were validated by molecular docking, surface plasmon resonance (SPR), and in vitro kinase assays. Functional effects were assessed in A549 and H1299 NSCLC cell lines using flow cytometry and Western blotting.

Artesunate was identified as a direct binder of CDK4, with molecular docking revealing a strong binding affinity (-7.069 kcal/mol). SPR analysis confirmed this interaction with a K_d of 488 μM, and in vitro kinase assays demonstrated potent inhibition of CDK4/Cyclin D3 activity (IC₅₀ = 0.2943 μM). Treatment with artesunate induced significant G0/G1 cell cycle arrest in both A549 and H1299 cells. This effect was mediated through inhibition of the CDK4-Rb-E2F axis, as evidenced by dose-dependent suppression of Rb phosphorylation at Ser780 and Ser795.

Our findings establish artesunate as a structurally distinct, non-aminopyrimidine CDK4 inhibitor with potent biochemical and cellular activity in NSCLC models. This work provides a promising therapeutic strategy to circumvent resistance associated with current CDK4 inhibitors and supports the repurposing of artesunate for CDK4-driven cancers.

Acral melanoma (AM) is an aggressive melanoma subtype with poor prognosis and limited response to immune checkpoint inhibitors (ICIs). Despite increasing research efforts, the mechanisms underlying therapeutic resistance remain incompletely understood.

This review examines the mechanisms driving immunotherapy resistance in AM, summarizes current clinical advances in combination regimens, and explores future therapeutic directions.

A narrative review of recent literature was undertaken, encompassing studies on resistance mechanisms and clinical trials investigating novel ICI-based combination therapies for AM.

AM exhibits distinct immunosuppressive microenvironment characterized by low tumor mutational burden, reduced CD8+ T-cell infiltration, enrichment of regulatory T cells, and specific genetic alterations. Emerging clinical data demonstrate that combination regimens-particularly dual ICIs (anti-PD-1 plus anti-CTLA-4) and ICI combinations with anti-angiogenic agents or chemotherapy-have shown promising efficacy, with some achieving superior response rates in AM patients.

Understanding resistance mechanisms is critical for identifying novel therapeutic targets and optimizing personalized strategies. Current evidence suggests combination therapies may overcome resistance and improve outcomes, though optimal regimens and sequencing require further investigation.

Continued research into innovative combination approaches and predictive biomarkers is urgently needed to improve survival in AM.

Covalently closed circular DNA (cccDNA), a stable episomal form of the hepatitis B virus (HBV) genome, functions as the transcriptional template for viral replication and persistence, posing a major barrier to HBV cure. While host DNA repair factors such as DDB2 and DNA polymerase delta (Pol δ) have been involved in cccDNA regulation in vitro, clinical validation remains limited. This study investigated the role of DDB2 and Pol δ in cccDNA maintenance using HBV-infected cell models and liver tissues from patients with HBV-related and occult HBV infection (OBI)-associated hepatocellular carcinoma (HCC). HepG2-NTCP cells infected with HBV were transfected with siRNAs targeting DDB2 or Pol δ, followed by quantification of intracellular cccDNA using droplet digital PCR (ddPCR). In liver tissues from HBV-HCC and OBI-HCC patients, the expression of DDB2 and Pol δ was assessed, while intrahepatic HBV DNA and cccDNA were measured by qPCR and ddPCR. Serum HBcrAg levels were evaluated using the iTACT-HBcrAg assay. Knockdown of DDB2 and Pol δ significantly reduced intracellular cccDNA levels (p = 0.010 and p = 0.006, respectively). In patient tissues, intrahepatic HBV DNA and cccDNA were markedly lower in OBI-HCC compared to HBV-HCC, despite comparable DDB2 and Pol δ expression. HBcrAg was detectable in 91.3% of HBV-HCC versus only 23.8% of OBI-HCC cases (p < 0.001). DDB2 expression correlated with intrahepatic viral markers in both groups and with HBcrAg only in HBV-HCC. These findings suggest that DDB2 is involved in cccDNA persistence and represents potential therapeutic targets for both overt and occult HBV-related HCC.

Human leukocyte antigen G (HLA-G) is a nonclassical major histocompatibility complex class I molecule whose increased expression has been consistently associated with unfavorable prognosis in solid tumors and has emerged as a potential immunotherapeutic target in hematological malignancies. HLA-G exhibits limited genetic diversity and generates multiple isoforms that play a critical role in immune tolerance, being physiologically expressed in immunoprivileged tissues and aberrantly upregulated in a variety of pathological conditions, including cancer. Accumulating evidence indicates that elevated HLA-G expression contributes to tumor immune evasion and influences clinical outcomes in patients with leukemia, lymphoma, and multiple myeloma. Genetic variability within the HLA-G gene, particularly polymorphisms located in regulatory regions such as the 14-base pair insertion/deletion, has been associated with cancer susceptibility, disease progression, and adverse prognosis. In hematological malignancies, specific genotypes, including the homozygous deletion variant, have been linked to increased levels of membrane-bound and soluble HLA-G, correlating with impaired immune surveillance and reduced survival, particularly in chronic lymphocytic leukemia. Moreover, HLA-G expressions may be modulated by inflammatory cytokines, such as interferon-γ, further shaping the immunosuppressive tumor microenvironment. By functioning as a nonclassical immune checkpoint, HLA-G represents a promising target for innovative immunotherapeutic strategies, including immune checkpoint blockade combinations and chimeric antigen receptor (CAR)-T cell approaches directed against HLA-G-expressing malignant cells. In this review, we summarize current knowledge regarding HLA-G expression, genetic polymorphisms, and immunoregulatory mechanisms in hematological malignancies, highlighting their clinical and translational implications. Improved understanding of HLA-G-mediated immune modulation may contribute to the development of novel prognostic biomarkers and therapeutic strategies aimed at restoring effective antitumor immunity.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer (PCa) that emerges following the androgen receptor (AR) targeted therapies. Identification of potential molecular drivers governing neuroendocrine differentiation (NED) and survival is critical for developing therapeutic strategies. Cancer-testis antigens of the Melanoma-associated antigen family (MAGE) are the emerging players of oncogenic regulators. However, their role in NEPC remains unexplored.

Proteomic and transcriptomic analyses were performed to identify differential expression of target proteins in NEPC. Functional characterization of MAGEA4 was performed using stable overexpression, siRNA-mediated knockdown in androgen-dependent/independent, and NEPC cell lines. For target validation, neuroendocrine markers, morphological characteristics, apoptotic signaling, oxidative pathways, and cell survival were evaluated using molecular, biochemical, and pharmacological approaches targeting SIRT1, p53 acetylation, BCL-2/BCL-XL and NRF2.

MAGEA4 was upregulated in NEPC cells and in advanced prostate cancer tissues. Overexpression of MAGEA4 induced neuroendocrine differentiation, promoted androgen-independent survival, and conferred resistance to apoptosis. Furthermore, MAGEA4 upregulated SIRT1 activity, which deacetylated p53, thereby suppressing pro-apoptotic signaling. Additionally, MAGEA4 enhanced the oxidative stress resistance through activation of the SIRT1/PGC-1α/NRF2 axis, suggesting a role in retaining the NED phenotype. In MAGEA4-positive cells, inhibition of BCL-2 and/or NRF2 attenuated the neuroendocrine characteristics, suggesting therapeutic vulnerability.

These findings highlight that MAGEA4 may contribute to neuroendocrine differentiation and survival in prostate cancer cells, and may represent a potential therapeutic vulnerability in aggressive prostate cancers.