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Bladder urothelial carcinoma (BLCA) exhibits heterogeneous outcomes, creating an urgent need for reliable prognostic biomarkers. Glycosylation modifications are crucial in cancer but understudied for BLCA stratification. Using clinical and transcriptomic data from The Cancer Genome Atlas (TCGA) and glycosylation-related genes from the Gene Set Enrichment Analysis (GSEA) database, we constructed a prognostic signature via LASSO regression. It was validated using receiver operating characteristic (ROC) curve and stratified survival analyses. The key gene, alpha-1,3-mannosyltransferase (ALG3), was experimentally validated. A novel 9-glycosylation-mRNA signature effectively stratified BLCA patients into distinct risk groups with significant overall survival differences. The model showed robust predictive accuracy (AUC) and remained independent of common clinicopathological factors. We identified ALG3 as central to the signature, confirming its elevated tumor expression and critical role in promoting cancer cell proliferation. We established a potent, glycosylation-based prognostic model for BLCA. Functional validation of ALG3 underscores glycosylation's biological importance in tumor progression and highlights its therapeutic potential.

Breast cancer is the most frequent malignancy and the second leading cause of cancer-related mortality in women. Estrogen receptor-positive (ER+) tumors are treated with endocrine therapies such as tamoxifen or aromatase inhibitors (AI), aimed at disrupting estrogen signaling. While these therapies are initially effective, resident tumor cells can develop resistance, leading to relapse. The p21-activated kinase 1 (PAK1), a regulator of oncogenic signaling pathways, has been implicated in tamoxifen resistance. However, it remains unclear whether PAK1 also affects the response to other endocrine therapies. Here we show PAK1 activity was elevated in tamoxifen-resistant and long-term estrogen-deprived MCF7 cell lines and showed enhanced responsiveness to EGF stimulation. Inhibition of PAK1 effectively reduced cell proliferation in both models, with distinct effects on PAK1 downstream substrates. In the tamoxifen resistance context, PAK1 inhibition induced activation of the pro-apoptotic protein BAD and triggered apoptosis while proliferation-related kinases were suppressed in the estrogen-deprived model. Our findings position PAK1 as a mediator of resistance to endocrine therapies suggesting that targeting PAK1 may present a novel strategy to overcome endocrine therapy resistance in ER+ breast cancer.

Endometriosis defined by the growth of endometrial tissues outside the uterus, affects women of reproductive age. A critical process in endometriosis progression, angiogenesis involves endothelial cell migration, proliferation and tube formation, with vascular endothelial growth factor (VEGF) playing a powerful role. Exposure to endocrine-disrupting pollutants, like Hexachlorobenzene (HCB) andChlorpyrifos (CPF), is linked to a higher risk of reproductive diseases including endometriosis. Both HCB and CPF are weak aryl hydrocarbon receptor (AhR) ligands. These study examined HCB and CPF mechanisms of action in endometriosis-associated angiogenesis in vitro. Our results show that HCB (0.005, 0.05 and 5 μM) and CPF (0.5-50 μM) induced VEGF secretion in human stromal endometrial cells (T-HESCs). Moreover, HCB- or CPF-conditioned media (HCB-CM, CPF-CM) from T-HESCs boosted endothelial cell (EA.hy926) proliferation and survival. In addition, wound healing assays rendered an increase in EA.hy926 cell migration after exposure to HCB-CM (0.005-0.5 μM) or CPF-CM (5 μM), while tube-like structures revealed an increase in neovasculogenesis after HCB-CM (0.5 μM) or CPF-CM (5 μM). Our findings show that HCB- and CPF-induced angiogenesis was mediated by AhR and VEGF receptor-2. These results demonstrate that both pesticides increase VEGF secretion in endometrial cells and triggers angiogenesis, a critical event in endometriosis progression.

Immunotherapy has emerged as a pivotal approach in cancer treatment, harnessing the body's immune system to recognize and eradicate tumor cells. The search for novel compounds that can enhance immune responses while selectively targeting cancer cells remains a significant area of research. This study investigates the immunotherapeutic and antitumoral potential of fatty acids derived from the subantarctic red macroalgae Sarcopeltis skottsbergii. The cytotoxic effects of these fatty acids were evaluated in vitro using HCC1954 (breast cancer), HL-60 (leukemia), and CHO (non-tumoral) cell lines. Results demonstrated significant inhibition of cell proliferation by MTT assay in HCC1954 and HL-60 cell lines (52% and 57.9% of growth inhibition, respectively), with no observed cytotoxicity in CHO cells. Cytotoxicity was also confirmed by fluorescence assay (LIVE/DEAD). Additionally, real-time PCR analysis conducted on the J774A.1 macrophage cell line and primary culture of mice splenocytes revealed increased expression of interleukins IL-4, IL-6, IL-10, IL-12, IL-17, TNF-α, and IFN-γ, which play a pivotal role in the immune system, indicating a balanced immune response that both mitigates excessive inflammation and promotes direct antitumor activity. These findings suggest that fatty acids from S. skottsbergii can adapt an immune response, contributing to the immunomodulation of the tumor. The absence of cytotoxicity in non-tumoral cells, combined with selective inhibition of cancer cell growth and immune activation, highlights the potential of S. skottsbergii fatty acids as a promising adjuvant in cancer therapy. These results underscore the value of natural compounds from marine sources in developing innovative immunotherapeutic strategies against cancer.

Obesity has emerged as one of the most significant global public health challenges of the twenty-first century and is now firmly established as a major risk factor for multiple cancer types. Hypertrophic adipose tissue generates chronic low-grade inflammation, adipose hypoxia, and fibrosis, which leads to activation of IL-6/STAT3, NF-κB, and PI3K/Akt/mTOR signaling. Hyperinsulinemia and insulin resistance increase oncogenic pathways, while dysregulated adipokines by elevated leptin and reduced adiponectin enhance proliferation, angiogenesis, epithelial mesenchymal transition, and immune evasion. Obesity further remodels the tumor microenvironment by promoting extracellular matrix deposition, angiogenesis, immunosuppressive cell expansion, and metabolic competition that impairs antitumor immunity. Emerging evidence also implicates obesity-driven epigenetic reprogramming, altered microbiome composition, and metabolic heterogeneity as key determinants of tumor aggressiveness and treatment response. Conventional oncologic therapies rarely account for host metabolic status, which may contribute to variable therapeutic efficacy in obese patients. This review integrates mechanistic and translational evidence to define actionable vulnerabilities within obesity-induced tumorigenic pathways. We evaluate targeted metabolic interventions, cytokine blockade, adipokine modulation, immune checkpoint optimization, microbiome-directed strategies, and precision stratification frameworks. The present review outlines a multidimensional therapeutic roadmap to improve prevention, treatment response, and long-term outcomes in obesity-associated malignancies.

Oncolytic viruses are promising cancer biotherapies but often show limited durability as single agents due to tumor-intrinsic resistance mechanisms. Because therapeutic efficacy is shaped by dynamic virus-tumor-stromal interactions, pharmacologic strategies that reprogram this interface may enhance virotherapy responses. Here, we investigate whether targeting tumor stress and survival pathways with triptolide and its prodrug Minnelide can enhance the oncolytic efficacy of measles virus in colorectal cancer. The in vitro effects of CD46 targeted (MV-GFP) and dual targeted (MV-CD46-muPA) oncolytic MV, alone and with Triptolide were assessed in human CRC cell lines. Mechanistic studies included gene expression analysis, functional proteomics, and western blotting. In vivo efficacy of MV-CD46-muPA combined with Minnelide was evaluated in HT29 and HCT116 xenografts. Biological effects were further characterized using transcriptomic profiling (RNA-seq), targeted gene expression (NanoString), and histological analysis. Triptolide enhanced MV mediated oncolysis in vitro, particularly in BRAF V600E mutant CRC cell lines, and modulated key cancer pathways including AKT, apoptosis and metabolism. In vivo, Minnelide significantly improved the efficacy of systemically administered MV-CD46-muPA in human CRC xenografts, with greater effects in BRAF mutant (HT29) models. The combination modulated cell cycle, metabolism, and survival associated genes, promoted apoptosis, and improved intratumoral viral distribution. These molecular effects resulted in reduced tumor cell proliferation (Ki67), decreased angiogenesis (CD31), and increased apoptosis (TUNEL) relative to single agents. Triptolide and Minnelide significantly enhance the oncolytic efficacy of measles virus in colorectal cancer, particularly in BRAF-mutant tumors in vivo, through reprogramming of virus-tumor-stromal interactions. This reprogramming arises from coordinated modulation of survival, metabolic, and stromal signaling pathways and is accompanied by improved intratumoral viral distribution. These findings position virus-tumor-stromal crosstalk as a central mechanistic axis of virotherapy response and provide a strong rationale for the translational and clinical development of rational virus-drug combination strategies in colorectal cancer and other malignancies.

Protein arginine methyltransferase 5 (PRMT5) is highly expressed in many cancers and is a potential therapeutic target. It is also expressed in the small intestine, suggesting a role in intestinal health. This study explores PRMT5's function in both normal physiology and radiation-induced intestinal injury (RIII), focusing on its effects on intestinal stem cells (ISCs) and their niche. We examined PRMT5 expression in healthy and radiation-damaged intestines and treated mice and organoids with AMI-1, a PRMT5 inhibitor. Epithelial lineage composition, ISC proliferation, inducible nitric oxide synthase (iNOS) levels, and organoid activity were assessed. The impact of PRMT5 deficiency on ISC function was studied in vitro, and RNA-Seq and qRT-PCR were used to explore its effects on the urea cycle. PRMT5 was highly expressed in intestinal crypts. AMI-1 treatment reduced small intestine length, altered epithelial morphology, and increased secretory cells. In healthy intestines, PRMT5 inhibition enhanced Olfm4 + ISCs and induced iNOS expression. After radiation, PRMT5 deficiency inhibited ISC proliferation and caused Paneth cell acidification in the ISC niche. Organoids showed reduced vitality. PRMT5 deficiency disrupted the urea cycle, upregulated iNOS, increased NO production, and elevated lipid and ROS levels, impairing ISC homeostasis. PRMT5 is critical for maintaining intestinal homeostasis and regeneration. Its deficiency disrupts ISC niche function, highlighting PRMT5 as a potential target for treating intestinal disorders.

Biomarkers, particularly prognostic and immune based, are lacking in colorectal cancer (CRC). This study aimed to evaluate the expression of novel immune based biomarkers among patients with CRC to predict clinical outcomes. A CRC tumor microarray (TMA) was developed from a multiracial patient population, and expression of diagnostic markers (CK7, CK20, CDX2) and immune based (HHLA2, B7-H3, PD-L1) determined by immunohistochemistry (IHC) in a novel quantitative manner. Comprehensive clinical information was extracted. Among patients with metastatic (m) cancers, Kaplan Meier curves were plotted, and Cox proportional hazards regression analysis was performed to evaluate association with overall survival (OS). Among 388 patients, 150 had de novo metastatic disease, 108 experienced relapses from localized cancer, and 130 patients had cured localized disease. Racially/ethnically, 70 were non-Hispanic whites (NHW), 159 were non-Hispanic blacks (NHB), 147 Hispanic, and 12 Asian. The median age was 62&#xa0;years, with a female predominance (53%). Among the patients with metastatic CRC, that included those with relapses and with de novo metastatic CRC (n&#x2009;=&#x2009;258), in a multivariable Cox proportional hazards model, left sidedness (HR 0.52; 95%CI 0.35 - 0.77, p&#x2009;<&#x2009;0.001) and low expression of both PD-L1 and B7-H3 was associated with better OS (HR 1.73; 95%CI 1.08-2.76, p&#x2009;=&#x2009;0.023). In this multiracial TMA of CRC, in a robust multivariable model, following REMARK guidelines, we validate our prior findings that low expression of both B7-H3 and PD-L1 is prognostic for OS among patients with mCRC. Given the rapid proliferation of B7-H3 targeted drug development in clinical trials, these findings may help create a platform for future research to delineate their predictive role in a bespoke therapeutic approach.

Hypertrophic scars (HS) are fibrotic skin disorders driven by abnormal fibroblast activity. The molecular mechanisms underlying HS remain incompletely understood, particularly the role of non-coding RNAs. Expression levels of lncRNA TUG1, miR-627, and IGF1R were measured in HS tissues and fibroblasts using qRT-PCR and Western blotting. Dual-luciferase assays validated direct interactions. Functional effects of TUG1 and miR-627 on fibroblast proliferation and migration were assessed using MTT and Transwell assays. A rabbit ear model of HS was used to examine in vivo effects of TUG1 and miR-627 modulation on scar formation and molecular expression. TUG1 was significantly upregulated in HS tissues and inversely correlated with miR-627, which was downregulated. TUG1 promoted fibroblast proliferation and migration by directly sponging miR-627, thereby lifting repression on IGF1R, a known pro-fibrotic effector. Luciferase assays confirmed direct binding of miR-627 to both TUG1 and IGF1R. Co-transfection of miR-627 attenuated TUG1-induced IGF1R upregulation and reversed its pro-fibrotic cellular effects. In vivo, TUG1 overexpression led to increased scar thickness, collagen deposition, and IGF1R expression, while miR-627 overexpression mitigated these effects. Co-administration of both restored scar morphology and molecular markers to near-control levels. TUG1 promotes hypertrophic scar formation by sponging miR-627 and derepressing IGF1R. This newly identified TUG1-miR-627-IGF1R axis plays a central role in HS pathogenesis and may serve as a promising therapeutic target for fibrotic skin disease.

Accumulating evidence indicates that diabetes is associated with increased risk of several cancers. The strongest evidence has been reported for cancers of the breast, colorectum, endometrium, liver, pancreas, and gallbladder. However, distinguishing causal relationships from associations driven by shared risk factors such as obesity, aging, and lifestyle behaviors remains challenging. Several biological mechanisms have been proposed to explain these associations. Key pathways include the effects of insulin resistance and compensatory hyperinsulinemia on mitogenic signaling pathways, including PI3K/AKT/mTOR and MAPK, as well as the influence of adiposity, chronic inflammation, and altered metabolic substrates on tumor initiation and progression. Hyperglycemia may also contribute by promoting tumor metabolism and cellular proliferation, although its independent contribution remains debated. These mechanisms likely interact to create a protumorigenic metabolic environment in individuals with diabetes. Obesity, which frequently co-occurs with diabetes, further amplifies these risks through altered adipokine secretion and increased estrogen production, highlighting the interrelated contributions of metabolic and hormonal factors. The relationship between diabetes and cancer has important clinical implications. Diabetes has been associated with worse cancer prognosis and higher cancer-related mortality, highlighting the importance of integrated management strategies. The impact of antihyperglycemic therapy on cancer risk and progression has been extensively studied, and ongoing research continues to evaluate potential protective or tumor-modifying effects. In this article, we summarize the epidemiologic and pathophysiologic evidence describing the relationship between diabetes and cancer and discuss strategies for risk mitigation, screening, and management.

CAR T cell therapy has demonstrated remarkable antitumor efficacy in hematologic malignancies, but its application in solid tumors remains challenging. This is primarily due to the suppressive tumor microenvironment, which impedes T cell infiltration and reduces their functionality. Compared with standard intravenous administration, localized delivery strategies offer significant promise for CAR T therapy in solid tumors. Nevertheless, most reported approaches rely on complex biomaterials and are mainly applied in immune-privileged tissues. Here, we developed an injectable, thermosensitive chitosan/&#x3b2;-glycerophosphate/gelatin (CS/G/GP) hydrogel for local delivery of GPC3-CAR T cells and the cytokine IL-15 to enhance therapeutic efficacy against solid tumors. This hydrogel not only supported in vitro survival and proliferation of CAR T cells but also limited passive diffusion of IL-15, thereby sustaining GPC3-CAR T cell activity, expansion, and cytotoxicity. In an in vivo NCG mouse model of hepatocellular carcinoma (HCC), hydrogel-mediated local injection markedly enhanced CAR T cell infiltration and antitumor activity within tumor tissues, without apparent systemic toxicity. Overall, our hydrogel platform offers a safe, feasible, and effective strategy for localized CAR T cell therapy, improving treatment efficacy in solid tumors.

Multidrug resistance (MDR) is one of the main causes of chemotherapy failure and cancer recurrence. Among the ATP-binding cassette (ABC) transporter family, ATP binding cassette subfamily C member 1 (ABCC1/MRP1) is a key member that significantly reduces intracellular drug accumulation by effluxing various chemotherapeutic drugs, leading to treatment failure. Recent studies have found that microRNA (miRNA) can inhibit ABCC1 expression at the post-transcriptional level by targeting its 3' untranslated region (3'-UTR) region, thereby affecting chemotherapy sensitivity. However, miRNA itself is regulated by upstream molecules, particularly circular RNA (circRNA), which acts as competing endogenous RNA (ceRNA) and can bind miRNA through the sponge mechanism, relieving their inhibition of ABCC1 and promoting the MDR phenotype. Multiple studies have identified specific circRNA/miRNA/ABCC1 regulatory axes in various cancers such as non-small cell lung cancer, colorectal cancer, breast cancer, and ovarian cancer. This axis is not only involved in chemotherapy resistance but also affects tumor proliferation, migration, and invasion. Due to their high stability and tissue specificity, circRNAs and miRNAs have potential as liquid biopsy biomarkers and therapeutic targets. Despite challenges posed by the complexity of the ceRNA network, intervention strategies targeting this axis, such as circRNA knockdown or miRNA mimics, are still considered important approaches to reverse cancer MDR. In addition, emerging computational approaches, such as graph learning, hypergraph networks, and pre-trained models, now enable large-scale prediction of circRNA-miRNA interactions, offering powerful tools to further dissect the regulatory axes underlying MDR.

Although poly (ADP-ribose) polymerase inhibitors (PARPi) have been established to enhance ovarian cancer outcomes, the emergence of drug resistance poses considerable clinical challenges. In this study, we constructed a Hi-C atlas to systematically characterize the effect of olaparib on chromatin organization at multiple hierarchical scales, namely, chromosomes, A/B compartments, topologically associating domains, and chromatin loops. To investigate the effects of PARPi on expression of the cohesion subunit RAD21, we established olaparib-resistant ovarian cancer cell line. Furthermore, we examined the effects of RAD21 on the functions of ovarian cancer cells and spheroids based on cell proliferation, apoptosis, and comet assays. In addition, by performing integrated analyses using ChIP-seq datasets, ChIP-qPCR, and chromosome conformation capture assays, we assessed the influence of RAD21 on the enhancer-promoter interactions of a homologous recombination repair gene. Moreover, on the basis of our findings in previous studies using clinical samples, we further evaluated the clinical value of RAD21 in multiple databases. Genome-wide Hi-C heatmap analysis revealed that olaparib led to a reduction in the genome-wide contact frequency for long distance interactions, altered the degree of chromatin compartmentalization, and promoted compartment switching in ovarian cancer. Differences between the olaparib-treated and control cells with respect to topologically associating domain boundaries and chromatin loops were found to be associated with key cellular functions, such as DNA repair and transcriptional mis-regulation in cancer. Furthermore, PARPi treatment was observed to induce the expression of RAD21, whereas an upregulation of RAD21 promoted proliferation and inhibited apoptosis in ovarian cancer spheroids. Mechanistically, we obtained evidence to indicate that by maintaining enhancer-promoter interactions within chromatin conformation, RAD21 regulates the transcription of RAD51, thereby mediating olaparib resistance in ovarian cancer. The high expression of RAD21 was found to show a significant association with poor overall and progression-free survival in patients with ovarian cancer. Our findings in this study indicate that RAD21 could serve as a potential therapeutic target for overcoming olaparib resistance in ovarian cancer, and provide new insights into the mechanisms underlying the resistance to PARPi from the perspective of chromatin organization.

Peptidyl arginine deiminase 4 (PAD4) catalyzes the deamination of arginine residues to citrulline, a post-translational modification known as citrullination, which regulates protein structure, function, and localization. Despite growing evidence connects PAD4 to cancer progression, its role in intrahepatic cholangiocarcinoma (ICC) remains largely unexplored. This study aimed to elucidate the role and underlying mechanisms of PAD4 in the regulation of intrahepatic cholangiocarcinoma proliferation, as well as to explore its clinical relevance and therapeutic potential. Hydrodynamic tail vein injection (HTVI) and subcutaneous xenograft models were used to evaluate the role of PAD4 in vivo. In vitro functional assays were performed to assess the effects of PAD4 on ICC cell proliferation. Putative targets were identified by RNA-seq and Co-IP/MS analyses. Molecular interactions were examined using GST pull-down, surface plasmon resonance (SPR), and RNA immunoprecipitation-PCR. The clinical relevance of PAD4 was evaluated in ICC patient samples using immunohistochemical analysis. PAD4 was identified as a key promoter of ICC proliferation by enhancing post-transcriptional expression of the MCM complex. Mechanistically, PAD catalytic domain of PAD4 interacted with the KH1 domain of IGF2BP2 and catalyzed its citrullination at R597, which markedly increased the affinity of IGF2BP2 for m6A-modified MCM2-7 transcripts, thereby stabilizing and elevating MCM mRNAs expression. Clinically, high PAD4 expression correlated with poor prognosis in ICC patients, while PAD4 and IGF2BP2 co-expression predicted worse outcomes. In vivo, combined inhibition of PAD4 and IGF2BP2 synergistically suppressed ICC growth. Our findings identify a tumor-intrinsic PAD4-IGF2BP2 axis that drives ICC progression through citrullination-dependent stabilization of MCM transcripts. Dual targeting of PAD4 and IGF2BP2 represents a promising therapeutic strategy for ICC.

Chromosomal instability (CIN), characterized by frequent changes in chromosome number and structure, is common in human carcinomas and often leads to aneuploidy, an unbalanced number of chromosomes. Drosophila has been instrumental in demonstrating that CIN can promote tumour growth and malignancy through aneuploidy-induced senescence, a state marked by cell-cycle arrest and high secretory activity. Despite extensive chromosomal heterogeneity, we show that these cells share a distinct transcriptional programme, with most responses to aneuploidy and senescence regulated at the transcriptional level. We unravel a pro-survival function of the Hippo-Yorkie signalling pathway in aneuploidy-induced senescent cells and present evidence that nearly 10% of the most upregulated genes encode secreted proteins of the senescence-associated secretory phenotype. Five of these proteins act additively, locally or systemically, to block proliferation and induce cell death in neighbouring tissues. This non-autonomous cell death feeds back to the tumour to enhance its growth, resembling super-competition and providing insight into tumour-host interactions relevant to human cancer.

Malignant tumor tissues with high proliferative activity are frequently characterized by a rich abundance of cancer-associated fibroblasts (CAFs). Nevertheless, the precise molecular mechanisms by which CAF-tumor cell crosstalk drives malignant proliferation remain incompletely elucidated. In this study, we demonstrate that exosomal microRNAs derived from lung adenocarcinoma cells reprogram adjacent normal fibroblasts into CAFs through downregulation of their common target, FOXN3. Suppression of this transcriptional repressor enhances the expression of genes associated with cell migration and extracellular matrix remodeling, thereby potentiating CAF infiltration into the tumor core. The consequent spatial proximity between CAFs and tumor cells enables the aberrantly altered secretome of CAFs to exert robust paracrine effects on malignancy. By focusing on receptors that interact with these dysregulated secreted proteins, we evaluated the drug sensitivity of patients bearing highly proliferative tumors to receptor-targeting agents, revealing potential therapeutic opportunities. Collectively, our work offers a detailed molecular dissection of tumor cell proliferation and proposes translationally relevant strategies for cancer therapy.

Despite its remarkable efficacy in hematologic malignancies, chimeric antigen receptor T-cell (CAR-T) therapy is often limited by atypical clinical outcomes, necessitating predictive biomarkers. Here, prompted by a patient with low-tumor-burden non-Hodgkin lymphoma who develops severe and persistent cytokine release syndrome (CRS), we identify the germline TNFR2M196R single-nucleotide polymorphism, rs1061622, as a candidate genetic determinant of atypical responses. The TNFR2M196R variant is found to enhance the antitumor efficacy of CAR-T cells by reducing their apoptosis. Paradoxically, however, patients carrying the TNFR2M196R variant exhibit higher rates of early tumor progression. Further investigation reveals that while the TNFR2M196R mutation increases tumor susceptibility to CAR-T-mediated killing, it also accelerates tumor proliferation kinetics. Together, these results establish the TNFR2M196R SNP as a dual-function genetic determinant that modulates both CAR-T cell efficacy and intrinsic tumor behavior, highlighting the critical impact of germline genetics on cancer immunotherapy.

Triple-negative breast cancer (TNBC) harbors an immunosuppressive tumor microenvironment dominated by tumor-associated macrophages (TAMs). P2RY6, a UDP-sensitive purinergic receptor, is implicated in immune modulation, but its functional role in TNBC TAMs remains elusive. The clinical relevance of P2RY6+ TAMs was assessed via bioinformatics, tissue microarrays, and survival analysis. In vitro, P2RY6 function in macrophage polarization, signaling, and paracrine regulation of TNBC cells was evaluated using genetic/pharmacological approaches, RNA sequencing, calcium imaging, and secretome analysis. The downstream effector S100A9 and its receptor (TLR4/RAGE)-NF-&#x3ba;B axis in TNBC cells were validated. Orthotopic TNBC mouse models were used to evaluate therapeutic targeting of P2RY6 and S100A9 in vivo. P2RY6&#x207a; TAM infiltration correlates with poor prognosis in TNBC patients. UDP activation of P2RY6 drives M2-like macrophage polarization via the PLC-IP3-Ca2+/CREB1 pathway, leading to transcriptional upregulation and secretion of S100A9. Macrophage-derived S100A9 binds TLR4/RAGE on TNBC cells, activates NF-&#x3ba;B signaling, and promotes tumor proliferation. Genetic or pharmacological inhibition of P2RY6, or neutralization of S100A9, suppresses TNBC growth in vitro and in vivo, and synergizes with chemotherapy to enhance antitumor efficacy. Our study unveils a UDP-P2RY6-S100A9 paracrine axis wherein P2RY6&#x207a; TAMs foster an immunosuppressive and pro-tumorigenic niche in TNBC. This axis represents a novel therapeutic target to disrupt TAM-tumor crosstalk and overcome chemoresistance in TNBC.

Skin cutaneous melanoma (SKCM) continues to pose significant therapeutic challenges owing to its aggressive nature and evolving resistance mechanisms. This study investigates the under-characterized role of Hippo pathway effector TEAD4 in SKCM pathogenesis through integrated multiomics analysis of clinical cohorts (TCGA, GEO, immunotherapy cohorts) combined with functional validation in A375 cell models and xenograft systems. Our pan-cancer analysis identified TEAD4 overexpression as a strong prognostic indicator associated with poor survival and a potential association with inferior immunotherapy response. Functional experiments in A375 cells and xenograft models showed that TEAD4 knockdown impaired proliferation, migration and tumour growth while increasing necroptosis-related markers. Mechanistic investigation showed that TEAD4 directly binds the COL1A2 promoter and promotes its transcription. In A375 cells, COL1A2 overexpression attenuated TEAD4 knockdown-induced changes in AKT/mTOR signalling, necroptosis-related markers and malignant phenotypes. These findings support a TEAD4 and COL1A2 regulatory model associated with SKCM progression, AKT/mTOR pathway activity and necroptosis-related phenotypes, and suggest TEAD4 as a prognostic factor and potential biomarker associated with immunotherapy outcome that requires further validation.