Colorectal cancer (CRC) is the third most prevalent malignancy globally, with its incidence and mortality rates exhibiting a consistent upward trend. It is commonly diagnosed at an advanced stage, constraining the available therapeutic strategies. Despite extensive research on CRC development and treatment, its specific pathological mechanisms are still not fully understood, and existing therapies face limitations. As one subtype of programmed cell death (PCD), pyroptosis is increasingly connected to complex interactions in cancer. Driven by the gasdermin (GSDM) family, pyroptosis plays context-dependent dual roles in CRC: it can promote tumorigenesis via sustained chronic inflammation and an immunosuppressive tumor microenvironment (TME), or suppress tumors through direct cancer cell killing and antitumor immunity activation. To build on prior work, this review systematically integrates its core molecular mechanisms, context-dependent dual roles, pathway crosstalk (apoptosis, ferroptosis, PANoptosis), and multilevel regulatory networks (gut microbiota, metabolism, epigenetics, non-coding RNAs (ncRNAs)), which have rarely been synthesized cohesively. We explore the clinical implications, with a focus on pyroptosis-based therapeutic strategies (chemotherapy sensitization, natural compounds, nanomedicines, photodynamic therapy (PDT)/sonodynamic therapy (SDT)) and their translational potential, while addressing the critical challenge of balancing their dual effects-an aspect that has not been fully elaborated in previous reviews.

Pituitary Neuroendocrine Tumors (PitNETs) are the most frequently diagnosed intracranial neoplasms in adults. The World Health Organization's 2022 fifth edition classification of pituitary neuroendocrine tumours (PitNETs) maintains an immunohistochemistry based taxonomy that places molecular biology at the centre of diagnosis. This framework provides a solid basis for subtype classification and therapy development. Methylation, defined as the transfer of a methyl group (CH₃) to DNA bases, histone side chains, or RNA nucleotides, is an epigenetic modification that has emerged as a key mechanism in neoplastic transformation. In this review, we synthesise current knowledge on histone, DNA, and RNA methylation in pituitary tumourigenesis, describing their distinct roles and mutual molecular crosstalk. By examining how these epigenetic modifications promote tumour initiation and progression, we assess their potential as drug targets and their translational applicability. Our objective is to propose new research directions and precision treatment strategies that exploit methylation related vulnerabilities, with the goal of improving clinical outcomes for patients with PitNETs.

Malignant tumors currently pose a significant threat to global health. Tumor progression is jointly regulated by genetic mutations and the mechanical properties of the tumor microenvironment (TME), including increased tissue stiffness, elevated fluid pressure, and mechanical compression experienced by circulating tumor cells (CTCs) within microvessels. These mechanical signals are transmitted through mechanosensitive pathways, with the Piezo channel family (Piezo1/Piezo2) serving as a core mediator.With their propeller-like trimeric structure, Piezo channels sense membrane tension, mediate calcium influx, and activate downstream signaling pathways (e.g., MAPK, PI3K/AKT/mTOR, YAP/TAZ), thereby regulating tumor cell proliferation, migration, immune microenvironment remodeling, and cancer stem cell-like transformation. Its expression exhibits tissue specificity and correlates with tumor staging, invasiveness, and pro gnosis.

Immune modulatory vaccines (IMVs) are an emerging class of immunotherapies designed to expand anti-regulatory T cells (anti-Tregs) that selectively target immunosuppressive elements within the tumor microenvironment (TME). Unlike conventional cancer vaccines aimed at tumor-associated antigens on malignant cells, IMVs target tumor microenvironment antigens (TMAs), such as indoleamine 2,3-dioxygenase (IDO), PD-L1, arginase-1 (ARG1), and transforming growth factor-β (TGF-β), which are expressed by malignant, myeloid, regulatory, endothelial, and stromal populations. IMVs elicit both CD8⁺ and CD4⁺ T-cell responses: CD8⁺ T cells can mediate cytotoxic elimination of TMA-expressing suppressive cells, whereas CD4⁺ T cells can induce proinflammatory cytokine programs that reprogram myeloid and stromal compartments toward immune-permissive states. Through these combined cytolytic and modulatory mechanisms, IMVs remodel suppressive cellular networks, improve antigen presentation, enhance immune infiltration, and amplify endogenous tumor-specific immunity. Early-phase clinical studies targeting IDO and PD-L1 have shown robust immunogenicity, favorable tolerability, and encouraging activity across multiple solid tumors, particularly in combination with immune checkpoint blockade. A phase III study in first-line advanced melanoma recently demonstrated that a therapeutic vaccine, when combined with anti-PD-1 therapy, can improve progression-free survival in patients with metastatic disease. The strongest signal was observed in PD-1-naïve disease and in PD-L1-negative tumors. Next-generation IMVs directed against ARG1 and TGF-β aim to address immune exclusion and desmoplastic stroma and are being developed across peptide- and mRNA-based platforms with favorable safety profiles that support evaluation in earlier-stage settings. Beyond oncology, analogous microenvironment antigens are induced in chronic and acute infections, suggesting that IMV principles may generalize to settings where regulatory circuits constrain pathogen clearance.

Surgery has been the primary treatment modality for patients with stage I non-small cell lung cancer (NSCLC) with limited to no role for adjuvant systemic therapy. However, 10% to 30% of patients with completely resected stage I NSCLC will recur, with higher risk of recurrence in tumors with higher maximum standardized uptake value, lymphovascular invasion, visceral pleural invasion, and International Association for the Study of Lung Cancer grade. Forthcoming trials of targeted therapies and immunotherapies may expand the role of adjuvant systemic therapy for patients with stage I NSCLC in the future.

Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 overexpression. Historically, treatment options for TNBC have been limited, because of the absence of actionable targets. The addition of immune checkpoint inhibitors to chemotherapy improved outcomes for a subset of patients with metastatic PD-L1-positive disease; however, a critical need for more effective therapies remains. Antibody-drug conjugates (ADCs) have been a promising advance in the management of advanced TNBC and are reshaping the landscape as they move earlier into the treatment algorithm. A greater understanding of the molecular heterogeneity of TNBC has enabled the pursuit of more targeted and personalized therapeutic strategies. Despite this, TNBC continues to have the least favorable outcomes compared with other breast cancer subtypes. This review highlights current evidence and future challenges in advanced TNBC, including optimizing therapeutic sequencing and the ongoing need for predictive biomarkers and novel agents.

Leiomyosarcoma (LMS) is a rare and aggressive smooth muscle tumor, and venous leiomyosarcoma (VLMS) is an uncommon subtype, with majority of the cases involving the vena cava. We report a case of a 56-year-old patient initially diagnosed as deep vein thrombosis (DVT) in the common femoral vein who was later diagnosed with primary VLMS originating from the deep femoral vein. Despite anticoagulation therapy, leg edema persisted and imaging studies revealed an intraluminal mass with increased extent and size. Initial duplex ultrasound suggested chronic DVT; however subsequent contrast-enhanced computed tomography and magnetic resonance imaging performed during follow-up demonstrated interval growth of an intraluminal mass, and positron emission tomography-computed tomography later confirmed metabolically active disease, leading to the diagnosis of VLMS. Surgical resection of the mass was performed, followed by reconstruction of the femoral vein using an expanded polytetrafluoroethylene graft. Histopathologic examination confirmed the diagnosis of LMS. The patient had an uneventful postoperative recovery and was referred for adjuvant therapy, including chemotherapy and radiotherapy. This case highlights the importance of a multimodal diagnostic approach in differentiating neoplasms from blood clots and underscores the need for a high level of suspicion when DVT presents with atypical features. Early diagnosis and wide surgical excision with the aim of achieving negative margins are essential for successful management of VLMS.

Primary pulmonary epithelioid trophoblastic tumor (ETT) without a uterine primary is exceptionally rare, with merely 29 cases documented in the English-language literature. Therefore, a standardized management protocol has yet to be established, and the optimal treatment strategy remains poorly defined.

Aggressive brain tumors such as glioblastoma (GBM) remain among the most lethal human cancers, with a median survival of only 15 months despite multimodal treatment. Their resistance arises from a triad of barriers-the blood-brain barrier (BBB), marked intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment (TME). Immunotherapeutic strategies based on natural killer (NK) and T cells, leveraging antigen-independent cytotoxicity and antigen-specific precision, respectively, offer potential breakthroughs but are often limited by chronic neuroinflammation. A key driver of TME suppression is prostaglandin E2 (PGE2), produced via the cyclooxygenase-2 (COX-2) pathway. PGE2 exerts a dual role: Intracellularly, it can promote apoptosis, whereas extracellularly, it fosters tumor progression, immune evasion, and therapeutic resistance. Through activation of EP2 and EP4 receptors, PGE2 signals via Gαs proteins to elevate cyclic adenosine monophosphate (cAMP), leading to impaired cytotoxic immunity. This signaling downregulates NK cell activating receptors (e.g., NKG2D, NKp30), induces CD8⁺ T cell exhaustion, and promotes regulatory T cell expansion. The COX-2/PGE₂ axis further mediates resistance to checkpoint inhibitors, CAR-T therapy, and chemotherapy by enhancing neuronal excitation through EP1 receptor activation in GBM. Targeting this pathway has therefore emerged as a compelling therapeutic strategy, which can restore NK and T cell function and sensitize tumors to immunotherapy. Combining PGE₂ modulation with next-generation NK/T cell approaches-including CAR-NK and CAR-T platforms-holds promise to overcome immune resistance and redefine therapeutic paradigms for GBM and other central nervous system malignancies.

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.

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.

Alzheimer's disease (AD) and glioblastoma multiforme (GBM) are biologically distinct age-related brain disorders with opposing clinical phenotypes. AD is characterised by progressive neurodegeneration and cognitive decline, whereas GBM is characterised by aggressive cellular proliferation and a poor prognosis. Despite these differences, converging evidence indicates that both conditions share molecular pathways and network-level dysfunction that emerge during brain ageing. Central to this convergence are G protein-coupled receptors (GPCRs), which act as integrative signalling hubs that regulate inflammation, metabolism, calcium (CA2+) homeostasis, and cell survival. In AD, GPCR signalling modulates amyloid-β production and clearance, Tau phosphorylation, intracellular CA2+ dynamics, and glial-driven neuroinflammation. In contrast, the same receptor families promote tumour growth, angiogenesis, immune evasion, and therapeutic resistance in patients with GBM. Core intracellular cascades, such as PI3K-AKT-mTOR and MAPK-ERK, are dysregulated in both diseases and function as shared signalling backbones, with outcomes dictated by cellular context rather than receptor identity. CXCR4, LPA₁, and FPR1 exemplify this duality, driving either oncogenic proliferation or neuronal dysfunction, depending on the biological environment. Recent advances in integrative multiomics, computational modelling, artificial intelligence, and organoid systems have revealed GPCR-centred regulatory nodes and accelerated the identification of druggable targets. Collectively, these findings suggest that AD and GBM, although pathologically antithetical, share a molecular fingerprint shaped by ageing-associated inflammation, metabolic disruption, cellular senescence and dysregulated GPCR networks. Deciphering this context-dependent duality may enable precision therapeutic strategies to either restore neuronal integrity in AD or suppress malignant programmes in GBM while fostering cross-fertilisation between neurodegeneration and neuro-oncology research.

Glioblastoma (GB), defined as IDH-wildtype CNS WHO grade 4 tumour according to the 2021 WHO classification of CNS tumours, remains a uniformly lethal malignancy in which the efficacy of temozolomide (TMZ) continues to be constrained by both intrinsic tumur biology and the pharmacological barrier imposed by the blood-brain barrier (BBB). Given the central role of the ABCB1 (MDR1/P-glycoprotein) efflux transporter in regulating CNS drug disposition, germline variation in ABCB1 has been proposed as a potential determinant of interindividual variability in TMZ response. This systematic review synthesised clinical evidence from four independent studies, encompassing more than 400 GB patients, evaluating the association between ABCB1 polymorphisms and TMZ efficacy and patients' survival. Across the available literature, the influence of ABCB1 genetic variation emerged as limited and inconsistent. An early study reported a marked survival advantage for carriers of the ABCB1 C1236T C/C genotype treated with TMZ, suggesting reduced efflux and enhanced drug exposure. However, subsequent investigations, including epigenetic analyses, high-quality multivariate survival modelling and a pharmacokinetic study demonstrating genotype-dependent differences in plasma TMZ concentrations, did not replicate a corresponding survival effect. Across the remaining cohorts, common variants such as 1236C>T, 2677G>T/A, 3435C>T and 1199G>A showed no robust association with clinical outcome, indicating that transporter-mediated modulation is likely overshadowed by dominant prognostic drivers, including MGMT methylation, IDH status and tumour heterogeneity. Collectively, current evidence does not support ABCB1 polymorphisms as reliable predictive biomarkers of TMZ response in GB. Nonetheless, the pharmacokinetic signals observed, together with emerging technologies capable of selectively modulating efflux activity at the tumour-BBB interface, point to a continued role for ABCB1 in future therapeutic strategies. Integration of transporter genomics with spatial pharmacokinetics and molecular stratification will be essential to refine drug delivery and improve outcomes in GB.

Neoadjuvant therapy has become one of the standard treatment modalities for various solid tumors. Accurate assessment of pathological response after neoadjuvant therapy is crucial to the guidance of subsequent treatment strategies and the determination of patient prognosis. Currently, expert consensus on pathological evaluation of neoadjuvant therapy efficacy has been well-established for tumors such as breast cancer and non-small cell lung cancer. However, the significant heterogeneity and multifocality of prostate cancer pose unique obstacles to establishing a standardized system for the pathological assessment for neoadjuvant hormonal therapy (NHT), The current status and challenges of pathological assessment for NHT response in prostate cancer are reviewed in this article, and the clinical value of predictive biomarkers is explored. The overarching goals are the optimize of patient stratification and the advance of precision medicine for prostate cancer.

The treatment landscape for treating NSCLC and SCLC has been shaped by significant advances in imaging, radiotherapy technology, tumor biology, and systemic therapy. This review evaluates the role of radiotherapy in contemporary lung cancer management, drawing on evidence from key prospective trials conducted in the past 2 decades.

Second primary cancers (SPCs) pose an increasingly significant clinical challenge for survivors of hematologic malignancies, attributed to improved therapeutic outcomes and prolonged survival. The development of SPCs is influenced by a complex interplay of treatment-related factors, genetic susceptibility, immune dysregulation, and microenvironmental remodeling. This narrative review summarizes the epidemiological patterns of SPCs in survivors of hematologic malignancies and discusses the underlying biological mechanisms, including therapy-induced genomic instability, clonal hematopoiesis, inflammatory signaling, and alterations in the bone marrow microenvironment. Furthermore, we review current surveillance strategies and emerging biomarkers for early detection and risk stratification. Additionally, we discuss the potential contributions of integrated multi-omics approaches, tumor microenvironment profiling, and precision medicine strategies to SPC monitoring and prevention. Lastly, we outline future directions for clinicians and researchers, emphasizing the necessity for personalized surveillance programs, translational biomarker validation, and multidisciplinary management strategies to mitigate SPC risk in long-term survivors.

The tumor microenvironment (TME), composed of tumor cells together with stromal cells, immune cells, vascular networks, and other components, constitutes a complex ecosystem that plays a decisive role in tumor initiation, progression, metastasis and therapeutic response. Traditional pathological diagnosis mainly relies on pathologists manually examining H&E-stained tissue sections under the microscope, a method that not only suffers from substantial interobserver variability but also has relatively low analytical efficiency. With the rapid development of computational pathology, the integration of whole-slide imaging technology and deep learning algorithms has provided powerful tools for characterizing tumor microenvironment. These techniques enable automated characterization of cellular, spatial and molecular heterogeneity within the tumor microenvironment, providing integrated insights that advance precision diagnostics and improve prediction of therapeutic response and patient outcomes. Based on a comprehensive review of existing research, this paper highlights recent advances in deep learning-driven recognition of panoramic TME features from H&E slides and their clinical applications and further discusses both the translational potential and current limitations of this technology in oncology research and clinical applications.

Implementing a prognostic model in clinical practice requires assessing not just its accuracy but also how it may impact patient and healthcare outcomes. Evaluating these impacts requires clinical trials that are carefully designed to select, collect, and report key outcomes. However, there is currently no consensus on which outcomes are key to evaluating the impact of prognostication. Core Outcome Sets can standardise outcome selection, collection, and reporting, and thereby improve the comparability of studies. Our study aimed to develop a preliminary Core Outcome Set for evaluating the impact of prognostication on people living with advanced cancer.