Drugs with multiple anticancer mechanisms have shown promising applications in tumor treatment. Herein, we synthesized a series of ferrocene-pyrazole hybrids (8-11) to assess their anti-pancreatic cancer activities. Among them, compound 11 exhibited higher anti-cancer effects compared to other compounds and showed low toxicity to normal HK-2 cells. The hemolysis experiment shows that compound 11 exhibited low hemolytic activity. Proteomics and metabolomics studies have found that a total of 35 proteins and 58 metabolites (negative mode) showed significantly different abundances in BxPC-3 cells treated with 10 μM compound 11. Subsequent research unveiled that compound 11 eradicates pancreatic cancer cells through the activation of various mechanisms, including ferroptosis and metabolic pathways. These studies may stimulate the development of ferrocene-pyrazole hybrids and provide effective cancer treatment.

To evaluate the prognosis of patients with nonsmall cell lung cancer (NSCLC) who did not undergo surgery after neoadjuvant chemotherapy combined with immunotherapy (NACI). Patients were grouped according to subsequent treatment: radiotherapy (RT) or nonradiotherapy (non-RT), and the prognostic importance of positron emission tomography/computed tomography (PET/CT) was further assessed.

Clear cell renal cell carcinoma (KIRC), the most prevalent pathological renal cell carcinoma (RCC) subtype, makes up approximately 75%-84% of total cases. KIRC is characterized by high heterogeneity, high metastasis rates, and a poor prognosis. Its incidence rate has continued to rise in recent years. We sought to construct new prognostic models to optimize treatment decisions, improve clinical benefits, and explore potential therapeutic targets.

Kidney renal clear cell carcinoma (KIRC) is an aggressive malignancy with limited therapeutic options, highlighting the need for novel biomarkers and therapeutic targets. Although endoplasmic reticulum metallopeptidase 1 (ERMP1) has been implicated in cancer progression, its specific role, clinical significance, and underlying mechanisms in KIRC remain poorly defined.

Cholangiocarcinoma (CCA) is a highly aggressive malignancy. 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a mitochondrial enzyme involved in ketogenesis, has been linked to tumor progression, but its role in CCA remains unclear. HMGCS2 expression in CCA tissues was analyzed using TCGA data and immunoblotting (IB). Functional assays were performed in CCA cell lines (HuCCT-1 and RBE) and an in vivo xenograft model. Metabolomics explored HMGCS2-mediated metabolic changes. SIRT3-HMGCS2 interactions were examined via molecular docking, IF, CO-IP, GST pull-down, and CHX assays, with mutational analysis identifying interaction sites. IHC assessed clinical samples. HMGCS2 was downregulated in CCA. Overexpression inhibited proliferation and invasion, while knockdown promoted these effects, consistent in vitro and in vivo. Metabolomics showed HMGCS2 enhanced ketone body synthesis, and exogenous ketone bodies mimicked its antitumor effects. SIRT3 deacetylated HMGCS2 at K310 (with plasmid mutation assay), and low HMGCS2/SIRT3 expression correlated with poor patient survival. SIRT3-mediated deacetylation of HMGCS2 promotes ketone body synthesis, suppressing CCA progression. HMGCS2 is a potential therapeutic target for CCA.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. Although the hypoxia-inducible factor 1A (HIF1A) pathway is crucial in HCC progression, its regulatory mechanisms remain unclear as mutations in its primary regulator, von Hippel-Lindau tumor suppressor (VHL), are rare in HCC. We aimed to elucidate the role of proliferation and apoptosis adaptor protein 15 (PEA15), identified through proteomic analysis, as a regulator of the VHL/HIF1A pathway and a therapeutic target in HCC. Methods: Proteomic and genomic analyses of over 1,000 HCC samples were conducted, identifying PEA15 amplification. Functional validation involved in vitro and in vivo assays, including gene knockdown, ectopic expression, and antisense oligonucleotide (ASO) therapy in xenograft models. Protein interactions were assessed using immunoprecipitation and ubiquitination assays. Results: We identified 3 clinically distinct HCC subtypes and found that PEA15 was selectively amplified and highly expressed in the mesenchymal (MES) subtype, which exhibited the poorest prognosis. PEA15 acted as a regulator of the VHL/HIF1A pathway and a key oncogene in HCC. The amplification of PEA15 was significantly associated with the poor survival of HCC patients. Moreover, by interacting with the β-domain of VHL, PEA15 promoted HCC cell proliferation and migration by inhibiting VHL's interaction with the VHL/elongin C (ELOC)/elongin B (ELOB)/cullin 2 (CUL2) E3 ligase complex, destabilizing the complex and consequently activating HIF1A. Importantly, pharmacologically inhibiting PEA15 using PEA15 ASO drugs attenuated tumor burden and restored VHL function in a xenograft mouse model. Conclusions: This study identified PEA15 as a potential oncogene in HCC, regulating the VHL/HIF1A axis and driving tumor progression. Targeting PEA15 using ASOs offers a promising therapeutic strategy for HCC, particularly in the MES subtype. These findings provide a basis for further exploration of PEA15-targeted therapies to improve HCC outcomes.

Human leukocyte antigen E (HLA-E) plays a role in tumor immune escape and is associated with poor prognosis in neuroblastoma (NB). This study aimed to investigate the regulatory effect of suberoylanilide hydroxamic acid (SAHA) on HLA-E expression via the PERK/ATF4/CHOP pathway in NB.

Growing evidence suggests a link between the gut microbiome and papillary thyroid carcinoma (PTC), but the causal relationships and the impact on the tumor immune microenvironment (TME) are poorly understood. This study aimed to elucidate the causal role of specific gut microbes in PTC and uncover the underlying immunological and molecular mechanisms. We employed a multi-stage design, beginning with a two-sample Mendelian randomization (MR) analysis using large-scale GWAS data to infer causality. Findings were then validated in 450 PTC patients from The Cancer Genome Atlas (TCGA) by analyzing correlations between microbial abundance, gene expression, immune cell infiltration, and survival. Finally, the core mechanism was confirmed through extensive in vitro experiments with PTC cell lines. Our MR analysis identified a causal association between a genetically predicted higher abundance of the genus Terrisporobacter and an increased risk of PTC (Odds Ratio [OR] = 2.06, 95% Confidence Interval [CI]: 1.34-3.16). In the TCGA cohort, higher intratumoral signals of Terrisporobacter was significantly correlated with an immunosuppressive TME, characterized by increased infiltration of M2 macrophages (ρ = 0.25, p < 0.001) and decreased CD8+ T cells (ρ = -0.19, p = 0.008). Mechanistically, Terrisporobacter abundance was also strongly associated with the upregulation of the oncogene NTRK1 (ρ = 0.35, p < 0.001), which independently predicted poorer overall survival (Hazard Ratio [HR] = 2.15, p = 0.004). In vitro experiments confirmed that supernatant from Terrisporobacter culture not only upregulated NTRK1 expression and promoted PTC cell proliferation but also enhanced invasion and induced cell de-differentiation. Importantly, pharmacological inhibition of TRK signaling reversed the bacteria-induced aggressive phenotype. Our integrated analysis provides robust, multi-layered evidence for a causal role of Terrisporobacter in promoting PTC progression. We define a novel gut-thyroid axis where Terrisporobacter contributes to PTC development by upregulating the NTRK1 oncogene and shaping a pro-tumorigenic, immunosuppressive microenvironment. These findings reveal a new dimension of host-microbe interaction in thyroid cancer and highlight the TME as a key downstream target of microbial influence.

Colorectal cancer (CRC) ranks among the most prevalent gastrointestinal malignancies with liver metastasis being the primary cause of CRC-related death. Although surgical and chemotherapeutic interventions continue to improve, patients with hepatic metastases frequently experience recurrence and limited treatment benefits. Liver metastasis is driven by tumor heterogeneity and immune evasion. Therefore, defining the cellular composition of CRC liver metastases may help identify new therapeutic targets.

PIK3CA is one of the most frequently mutated genes in cervical cancer (CC). However, its clinical utility is hampered by paradoxical treatment-dependent outcomes, restricting its application in precision oncology. To address this issue, we constructed a high-resolution single-cell transcriptomic atlas of the CC tumor microenvironment. It was found that PIK3CA mutations induce a dichotomous TME, simultaneously associated with marked T-cell inflammation and resistance to adaptive immune responses. Malignant epithelial subsets induce CD8+ T-cell exhaustion through both canonical PD-L1-PD-1 signaling and the non-canonical SPP1-CD44 axis. Additionally, PIK3CA mutations enrich for MMP9+ macrophages that promote tumor angiogenesis through ANGPTL4 signaling. This dual landscape of T-cell exhaustion and active angiogenesis provides a framework for the observed synergy between PD-1 blockade and anti-angiogenic therapies. The findings demonstrate that the presence of PIK3CA mutations is a key predictive biomarker for guiding combination immunotherapy in CC and identify a rational basis for co-targeting distinct immune and vascular resistance pathways.

Tumor heterogeneity is a fundamental driver of therapeutic resistance across solid malignancies, arising from genetic, epigenetic, phenotypic, spatial, temporal, and microenvironmental diversity. In tumors developing at mucosal barrier sites, these heterogeneous features are further shaped by the unique immunological context of mucosal tissues, where immune tolerance, chronic inflammation, and continuous antigen exposure create permissive environments for immune escape and adaptive resistance. Accumulating evidence indicates that myeloid cell plasticity, including functional diversification of granulocytes, macrophages, monocytes, and dendritic cells, represents a critical interface between tumor-intrinsic heterogeneity and mucosal immune regulation. These myeloid populations contribute to spatially organized immunosuppressive niches, altered antigen processing and presentation, and therapy-induced immune remodeling, collectively influencing responses to chemotherapy, targeted therapy, and immunotherapy. Advances in single-cell sequencing, spatial transcriptomics, multiplex imaging, and liquid biopsy technologies, coupled with artificial intelligence-enabled analytics, have enabled high-resolution mapping of heterogeneous tumor immune landscapes and revealed convergent resistance mechanisms driven by clonal selection, phenotypic plasticity, microenvironmental buffering, and myeloid-mediated immune suppression. In this review, we synthesize mechanistic and clinical evidence across major cancer types, including colorectal and lung cancers as archetypal mucosal tumors, along with broader examples from breast cancer, melanoma, and immunotherapy-treated malignancies. We highlight how heterogeneous cellular states and immune niches influence clinical outcomes. Finally, we discuss emerging translational strategies to overcome resistance, including rational combination regimens, epigenetic and metabolic targeting, adaptive therapy, myeloid reprogramming approaches, and real-time biomarker monitoring. These approaches aim to restore effective anti-tumor immunity while accounting for the unique constraints of mucosal barrier tissue.

Fast-growing solid tumors exhibit aerobic glycolysis to meet metabolic demands and evade immune surveillance. While the tumor microenvironment (TME) plays a crucial role in supporting this glycolytic phenotype, the contribution of host metabolites remains incompletely understood.

Primary colon squamous cell carcinoma (SCC) is an extremely rare malignancy and associated with a poor prognosis. This case report describes a patient with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) ascending colon SCC, who was treated at our institution. After receiving four cycles of programmed cell death -1 (PD-1) blockade monotherapy, the tumor exhibited significant regression, and pathological complete response (pCR) was achieved following surgical resection. This case demonstrates that Anti-PD-1 therapy can induce clinically meaningful tumor regression even in this rare colon SCC subtype, suggesting a potential treatment strategy for dMMR/MSI-H colon SCC. These findings may provide valuable insights for clinicians managing similar cases. However, the feasibility and safety of immunotherapy in dMMR/MSI-H primary colon SCC require further validation through additional clinical studies.

The recent U.S. FDA approval of lifileucel, a non-engineered, autologous tumor-infiltrating lymphocyte (TIL) therapy, for unresectable or metastatic melanoma represents a major milestone for cellular therapies in solid tumors. This review examines the clinical foundation, regulatory development, limitations, and evolution of TIL therapy in metastatic melanoma. Randomized academic data from the phase III M14TIL trial established the efficacy of TIL therapy. The C-144-01 study leading to lifileucel approval demonstrated median duration of response of 36.5 months, median overall survival (OS) of 13.9 months, and estimated 5-year OS rate of 19.7%, a major advance in this anti-PD-1/PD-L1 resistant cohort without effective treatment options. Despite durable responses, classical TIL therapy requires intensive nonmyeloablative lymphodepletion and high-dose interleukin-2 (IL-2), contributing to substantial toxicity and treatment-related mortality that remain barriers to broader implementation. We discuss safety-driven trial terminations related to cytokine augmentation and feasibility or strategic factors underlying discontinuation of programs, underscoring translational challenges beyond biologic efficacy. Engineered TIL platforms aim to improve persistence and reduce systemic cytokine dependence. OBX-115, designed with regulatable membrane-bound IL-15 expression, eliminates the need for IL-2 infusion and has shown early clinical activity. KSQ-001EX uses CRISPR/Cas9 to inactivate SOCS1, while KSQ-004EX additionally targets Regnase-1 to enhance TIL function. Emerging strategies including IL-2-independent expansion platforms, PD-1-edited TILs, and neoantigen-enriched products illustrate ongoing innovation. TIL therapy remains among the most promising strategies in melanoma and solid tumors after immunotherapy failure. Ongoing research aims to optimize cell dose, phenotype, tumor procurement, treatment sequencing, and rational combinations to improve durable benefit.

The autophagy adaptor and scaffold protein p62 plays a critical role in colorectal cancer (CRC) progression. As a malignancy driven by chronic inflammation, CRC arises from the combined effects of oncogenic signaling activation, genetic mutations, and epithelial barrier disruption. During early stages of inflammation, p62 exerts tumor-suppressive functions by clearing inflammasomes, activating NRF2, and downregulating inflammatory cytokines. However, sustained inflammation leads to p62 accumulation, which reinforces the activation of NRF2, NF-κB, and mTORC1 pathways through positive feedback loops, thereby driving tumorigenesis. Excessive p62 also impairs DNA double-strand break repair, facilitating oncogenic mutations. These observations indicate that enhancing autophagic clearance of p62 could represent a promising therapeutic strategy to prevent inflammation-associated CRC.

Androgen deprivation therapy (ADT) has long been a cornerstone of treatment for patients with locally advanced or metastatic hormone-sensitive prostate cancer. The efficacy of ADT plus radiotherapy (RT) compared to ADT alone remains unclear due to conflicting results in existing literature. The study aimed to systematically evaluate the effectiveness of ADT combined with RT versus ADT alone in patients with prostate cancer (clinically node positive, locally advanced disease, metastatic disease), focusing on overall survival (OS), prostate-specific mortality (PSM), progression-free survival (PFS), and the risk of complications. A comprehensive search of PubMed, Embase, Web of Science, and Scopus was conducted between 1st January 2000 and 15th October 2024 to identify studies comparing ADT alone to ADT combined with RT. Hazard ratios (HRs) and relative risks (RRs) with 95% confidence intervals (CIs) were calculated for the outcomes. The certainty of the evidence was assessed using the standard GRADE approach. A total of 8 studies met the inclusion criteria (6 RCTs and 2 cohort studies). These studies included 18,456 patients. The combination of ADT and RT significantly improved OS (HR = 0.75, 95% CI, 0.63, 0.90), PFS (HR = 0.41, 95% CI, 0.20, 0.84), and reduced PSM (HR = 0.52, 95% CI, 0.34, 0.78) compared to ADT alone. Subgroup analysis showed greater OS (HR = 0.66, 95% CI, 0.59, 0.75) and PSM (HR = 0.43, 95% CI, 0.39, 0.49) in patients with locally advanced or node-positive disease. ADT + RT was also associated with increased risks of genitourinary (RR = 1.80, 95% CI, 1.15, 2.82), gastrointestinal (RR = 4.18, 95% CI, 1.46, 11.96), and sexual dysfunction-related complications (RR = 1.10, 95% CI, 1.02, 1.18). The overall certainty of evidence was judged to be 'moderate' for survival outcomes and 'low' for risk of complications. Combining ADT with radiation therapy RT significantly improved survival, compared to ADT alone, especially in patients with locally advanced or node-positive prostate cancer, yet with moderate GRADE certainty. However, this combination also increased the risk of complications. The results advocate that our findings are most applicable to high-risk non-metastatic and cN+ disease and do not support routine addition of RT to ADT in unselected metastatic patients. Therefore, further research is needed to refine treatment protocols and identify the optimal timing and patient subgroups for this approach.

Inflammation plays a critical role in tumor progression and drug resistance. Our previous research has repurposed carvedilol (CVL) to re-sensitize paclitaxel (PTX)-resistant gastric cancer AGS Cells (AGS-Rpac) to PTX. This study aimed to evaluate the effects of combined CVL and PTX therapy on the modulation of inflammatory mediators and their associated signaling pathways. AGS-Rpac cells were treated with specified concentrations of PTX and CVL. Levels of IL-1β and TNF-α were measured. The expression levels of nuclear factor kappa B (NF-κB p65), NLR family pyrin domain containing 3 (NLRP3), as well as the β2-adrenergic receptor (β2-AR), β-arrestin-2, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), were assessed by western blotting. CVL alone, and particularly PTX and CVL + PTX treatments, prompted a significant increase in NLRP3, NF-κB p65, IL-1β, and TNF-α inflammatory factors compared to the control. β2-AR expression was decreased in CVL-treated cells compared to other groups (p < 0.001). β-Arrestin-2 and cGAS levels were increased in CVL monotherapy, whereas they were reduced in the PTX-treated cells compared to the control. These protein levels were restored to near-control levels with combination therapy. STING expression was upregulated in the control and CVL groups. The diminished levels of STING in PTX-treated cells were slightly increased in combination therapy. The combination of PTX and CVL significantly increased levels of inflammatory factors. CVL appears to recruit β-arrestin-2 to β-adrenergic receptors, which, in turn, activate the cGAS-STING pathway and induce the production of inflammatory factors.

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) class I/II inhibitor that has been evaluated in clinical trials for efficacy in pediatric cancers. Previous studies demonstrated cellular responses to SAHA in retinoblastoma (RB), a pediatric intraocular cancer. However, its mechanism of action remains incompletely understood. In this report, we demonstrate that SAHA inhibition of cell proliferation and induction of cell death was associated with the downregulation of the FOXM1 oncogene in the MYCN-driven RB1-/RB1-cell lines WERI-RB1 and Y79, of which Y79 exhibits greater metastatic potential. SAHA also deregulated cell cycle genes that are targeted by FOXM1. Additionally, SAHA inhibited RB metastatic signaling, including inhibiting the expression of MMP2, a transcriptional target of FOXM1. Further, because SAHA inhibition of FOXM1 positively correlated with suppression of the MYCN oncogene, we demonstrated that genomic knockdown of MYCN in the RB cell lines resulted in FOXM1 downregulation. Finally, we showed that FOXM1 inhibition downregulated NF-κβ and inhibition of FOXM1 suppressed FOXM1 expression in the RB cell lines. Taken together, these results indicated that SAHA inhibition of FOXM1 oncogenic signaling may be mediated by MYCN in RB. Although the current data provide a preclinical rationale for the consideration of SAHA either as a single agent or in combination with other therapies, for the treatment of metastatic RB with MYCN-amplified RB1-/RB1-molecular phenotype, further research is warranted to gain greater insight into FOXM1-MYCN interaction in response to SAHA, in this molecular subtype of RB.

The objective of this study was to establish a new model for predicting the prognosis of endometrial carcinoma (EC) using tumor-infiltrating lymphocytes (TILs) based on artificial intelligence (AI).

Nondiagnostic cytology for thyroid nodules, consistent with The Bethesda System for Reporting Thyroid Cytopathology category I (B1) poses a management dilemma for clinicians. The objective of this study was to define the malignancy risk of nodules with B1 cytology using American College of Radiology Thyroid Imaging Reporting & Data System (TI-RADS) and to assess whether TI-RADS can help guide the decision to perform a repeat biopsy of these nodules.