This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of G12C-inhibitors compared to chemotherapy in second line and beyond in adults with advanced/metastatic non-small cell lung cancer (NSCLC) with a Kirsten rat sarcoma (KRAS) G12C mutation.

Venetoclax and hypomethylating agent combination therapy is now the standard of care in acute myeloid leukemia (AML) for patients ineligible for intensive therapy, including the elderly; however, venetoclax and low-dose cytarabine remain a viable option for select patients. Relapse in this cohort remains a significant challenge, with a poor prognosis and an unmet need for further treatment options. This case discusses an elderly patient with NPM1-mutated AML successfully retreated with time-limited venetoclax and low-dose cytarabine at relapse. The sustained response observed contributes to the limited literature on the efficacy of re-treatment with venetoclax-based therapy in this setting. However, prospective data are required to assess the efficacy and safety of this strategy as well as to establish the role of molecular monitoring. The role of time-limited venetoclax therapy for preventing treatment resistance and limiting treatment-related adverse effects remains an important question in the cohort ineligible for intensive therapies, given the poor prognosis and limited options of relapsed/refractory AML post-venetoclax and hypomethylating agent therapy.

Isolavonoides represent the second largest subgroup of flavonoids and have an influence on critical molecular pathways and restore cellular homeostasis, through the reprogramming of epigenetic regulatory mechanisms. This feature indicates a crucial therapeutic potential that could be better explored to attend cancer treatment. Isoflavonoids, acting as epigenetic modulators, could contribute to the development of new therapeutic approaches in cancer, especially in onco-hematological diseases. Pterocarpans are a subgroup of isoflavonoids that have been extensively studied for their biological properties. The molecule (+)-2,3,9-trimethoxypterocarpan demonstrates high gastrointestinal (GI) absorption and the ability to cross the blood-brain barrier (BBB) in silico without violating Lipinski's rule, making it a desirable candidate in leukemia treatment. The synthesis of this molecule dates back more than a decade. In silico models, such as SwissADME, corroborate the notion of good intestinal absorption and the ability to cross the BBB. Also, it is suggested that P-glycoprotein is a substrate, which is related to its potential for active efflux from both the BBB and GI. This review highlights the biological mechanisms of this class of natural products from a translational perspective, emphasizing their chemical properties and epigenetic biological activities, which offer new therapeutic perspectives, particularly in oncology.

Cervical carcinoma continues to be one of the leading causes of cancer-related mortality among women worldwide, disproportionately striking developing regions, including India. High-risk persistent HPV infection has long been recognized as the central etiological factor in cervical carcinogenesis; however, not all infected women end up with malignancy, indicating the role of viral genomic variation and host genetic susceptibility. High-risk HPV variants, primarily comprising lineage clusters of HPV16 and HPV18, exhibit differential oncogenic potential due to mutations in the E6/E7 oncogenes and the LCR, which is responsible for viral persistence, the efficiency of p53/pRb degradation, immune evasion, and epithelial cell transformation. Genetic polymorphisms in the host regulate the natural history of infection and cervical cancer risk. Variants of HLA class I/II alleles influence antigen presentation and Single nucleotide polymorphism in immune regulatory cytokine genes (IL-10, TNF-α, IFN-γ), TP53 codon 72 (Arg/Pro), DNA repair and metabolic genes (XRCC1, MTHFR), and detoxification gene null genotypes (GSTM1, GSTT1) modulate viral persistence, oxidative DNA damage response, and oncogenic progression. Advancements such as next-generation sequencing and immunogenetics, which identify the relationship between HPV variants and host immune genes that modulate disease susceptibility, vaccine responsiveness, and progression patterns across various genetic backgrounds. This review systematically integrates molecular mechanisms of HPV variant-induced oncogenesis and host genetic susceptibility with emphasis on population-based variability in addition to evidence culled from meta-analyses and GWAS data for immune regulation, DNA repair, as well as host single nucleotide polymorphisms in different populations and its implications for personalized prevention measures, screening, and vaccine response.

Cervical squamous cell carcinoma (SCC) is classified by the World Health Organization based on its association with human papillomavirus (HPV) into HPV-associated (HPVA) and HPV-independent (HPVI) categories. HPVI SCCs can be p53 wild-type or p53 abnormal, the latter harboring a driver alteration in TP53 and portending worse survival. Recent developments have expanded the spectrum of squamous intraepithelial lesions (SILs) in the cervix. In the HPVA category, seborrheic keratosis-like lesions are now established as having an aetiological association with HPV42, a common low-risk HPV type. Papillary immature metaplasia, a further low-risk HPVA lesion, also falls into this category. More recently, potential HPVI squamous precursor lesions have been described; these form a wide morphologic spectrum and are difficult to diagnose, with the use of p16, p53, and HPV testing mandatory. When these ancillary tests are used, the HPVI SILs, similar to their invasive counterparts, stratify into p53 abnormal and p53 wild-type categories. Different genomic alterations are seen within the two groups, supporting their neoplastic nature. In this review, we provide a historical perspective and comprehensive description of all cervical SILs, with a focus on emerging entities and premalignant lesions, and appraise the terminology used over past years and that recently proposed for new entities. Key clinical, colposcopic, and morphologic features, differential diagnosis, treatment, follow-up, and prognosis are discussed. Special attention is paid to ancillary studies that assist in resolving differential diagnoses and their interpretation in light of recent scientific publications and international guidelines. We also discuss the clinical impact of a pathologic diagnosis of HPVA versus HPVI SILs.

Cancer immunotherapy has markedly improved clinical outcomes for cancer patients. However, its broad application is constrained by low response rates, which limit therapeutic benefits to only a subset of individuals. A deeper understanding of the tumor microenvironment (TME) and the interactions between tumor and immune cells is crucial for overcoming resistance. In this context, the reprogramming of erythroid progenitor cells (EPCs) within the TME has emerged as an important mechanism of immunotherapy resistance. EPCs, a key population in erythroid differentiation, undergo epigenetic reprogramming that underlies various physiological and pathological states. Through epigenetic modifications, EPCs may interact with immune cells and thereby promote tumor immune evasion. This review summarizes EPC reprogramming in the TME from an epigenetic perspective and explores their crosstalk with tumor and immune cells. It also evaluates the therapeutic potential of epigenetic drugs targeting EPCs and discusses future research directions focused on reversing pathological epigenetic reprogramming in EPCs to enhance immunotherapy efficacy. These advances hold significant potential for optimizing clinical cancer care paradigms and improving patient prognosis.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death globally. Most CRCs arise from colorectal adenomas (CRAs), particularly advanced adenomas, which are recognized as critical precancerous lesions. Early detection and intervention at the adenoma stage are essential for alleviating the global disease burden of CRC. However, conventional screening methods such as colonoscopy are invasive and have poor compliance, underscoring the urgent need for efficient, noninvasive diagnostic alternatives. Blood-based biomarkers have gained substantial attention because of their accessibility, reproducibility, and potential for early detection. Advances in multiomics technologies including proteomics, metabolomics, transcriptomics, and epigenomics have led to the identification of numerous plasma- and serum-derived biomarkers. These include noncoding RNAs (e.g., microRNAs, circular RNAs, PIWI-interacting RNAs), DNA methylation signatures, disease-specific proteins, and metabolic profiles. Moreover, emerging platforms such as liquid biopsy, extracellular vesicle profiling, and machine learning further expand the landscape of early CRA detection. The integration of multiomics data holds promise for substantially increasing the sensitivity and specificity of early adenoma detection, offering a transformative framework for precise CRC screening and risk stratification.

The epitranscriptome, particularly N6-methyladenosine (m6A), represents a dynamic layer of post-transcriptional regulation fundamentally implicated in cancer. However, the clinical translation of this knowledge is hampered by profound context-dependency, where the same m6A regulator can exert opposing roles in different tumors. To overcome this barrier, we propose a novel, clinically actionable taxonomic framework that classifies tumors based on their dominant dysregulated m6A component.

This review explores the alterations in natural killer (NK) cell function in acute myeloid leukemia (AML) and their implications for disease progression and therapeutic outcomes. As key effectors of innate immunity, NK cells are critical in recognizing and eliminating malignant cells. In AML, however, NK cells frequently exhibit numerical and functional deficiencies, resulting in compromised immunosurveillance that facilitates tumor immune escape and disease advancement. We systematically examine the application of single-cell omics technologies in AML research to elucidate the omics profiles and phenotypic distribution of NK cells within the leukemic microenvironment, characterizing their dysfunctional state by upregulated inhibitory receptors, downregulated activating signals, an altered cytokine milieu, and complex cellular crosstalk within the bone marrow (BM) niche. Furthermore, this article correlates functional dynamics of NK cells with conventional and emerging treatments, including CAR-NK immunotherapy, underscoring their potential role in disease monitoring and prognostic stratification. We also discuss promising NK cell-based immunotherapeutic strategies for AML, emphasizing the potential of modulating or engineering NK cells to enhance antitumor immunity. A deeper understanding of NK cell biology and regulatory mechanisms in AML is essential for developing novel immunotherapies and improving patient prognosis.

Colorectal cancer (CRC) adjuvant therapy is evolving from tumor-node-metastasis stage-based strategies toward molecular-profiling-guided precision medicine. This minireview, based on a comprehensive literature search in PubMed and Web of Science using keywords related to CRC biomarkers and adjuvant therapy (from 2010 to 2025), examines how key biomarkers, including mismatch repair (MMR) status, rat sarcoma viral oncogene homolog/rapidly accelerated fibrosarcoma mutations, consensus molecular subtypes, and circulating tumor DNA, refine risk stratification and treatment selection. Despite consensus guidelines advocating individualized therapy, significant disparities persist in real-world implementation due to technical variability in testing, limited or evolving evidence for specific scenarios (e.g., adjuvant immunotherapy for MMR-deficient/microsatellite instability-high patients, wherein phase 3 trials such as ATOMIC have yet to report mature overall survival data), and health economic barriers. The minireview analyzes gaps across testing, decision-making, and dynamic monitoring phases, and proposes integrated solutions involving technological innovation (e.g., artificial intelligence-integrated multiomics, circulating tumor DNA monitoring), optimized clinical pathways, and supportive health policies. Bridging these gaps requires multidisciplinary collaboration to translate molecular insights into equitable, personalized adjuvant care for CRC patients.

As a major cause of cancer-related death globally, colorectal cancer (CRC) remains largely refractory to immunotherapy outside the context of microsatellite instability-high (MSI-H). This limited efficacy stems largely from the complex crosstalk within the tumor microenvironment (TME), which fosters immunosuppression and resistance. Our review analyzes the impact of dysregulated pathways-such as PD-1/PD-L1, cGAS/STING, Notch, and cytokine signaling-on the functional states of T cells, B cells, macrophages, dendritic cells, and NK cells in CRC. We investigate how these pathways underpin critical processes such as immune evasion, T cell exhaustion, and the protumor polarization of innate immune cells, thereby fostering a permissive niche for tumor growth and resistance to checkpoint inhibitors. The discussion also covers emerging biomarkers and innovative strategies, including combination therapies targeting pivotal signaling nodes, to reprogram the immune landscape. A deeper mechanistic understanding of these immunoregulatory pathways is essential for developing effective treatments to overcome resistance and improve patient prognosis.

Glomus tumor (GT) is a rare mesenchymal neoplasm presumed to originate from the neuromyoarterial glomus body. Its pathogenesis is complex and involves alterations in multiple genes and signaling pathways. In the era of precision medicine, increased molecular research has begun to elucidate the oncogenic drivers of GT, offering novel potential directions for targeted treatment strategies.

Dysregulation of the cell cycle is one of the fundamental mechanisms underlying tumorigenesis, making cell cycle-related regulators potential antitumor therapeutic targets. Despite significant advances in understanding cell cycle regulatory networks, there is still a lack of a comprehensive and up-to-date synthesis that integrates the latest mechanistic insights with their translational potential in oncology. This review first systematically outlines the pivotal role of the cyclin-cyclin-dependent kinase (CDK)-cyclin-dependent kinase inhibitor (CKI) axis in driving aberrant cell cycle progression in tumors. Then the complex regulatory mechanisms of the tumor cell cycle were explored from various perspectives, including transcriptional control, post-translational modifications, checkpoint mechanisms, crosstalk with cellular processes, and integration with key signaling pathways. Furthermore, we highlight a series of clinically relevant biomarkers tightly linked to cell cycle dysregulation. Focusing on approved therapeutic agents and natural compounds in clinical trials, current treatment approaches that target the cell cycle and related metabolic pathways were also comprehensively assessed, and their prospects in precision oncology were elaborated. Finally, we discuss persistent challenges, including the incomplete understanding of tumor-specific cell cycle networks and the barriers to the clinical translation of targeted therapies. We advocate for future research to leverage multi-omics integration and systems biology approaches to facilitate more precise and effective cell cycle-directed interventions. This work offers a comprehensive framework that connects the fundamental mechanisms of cell cycle dysregulation in tumors with clinical translation, aiming to accelerate biomarker discovery and the development of next-generation precision oncology strategies.

Lipid metabolism is essential for maintaining cellular homeostasis, and its dysregulation is linked to various diseases, including cancer, cardiovascular disease, and diabetes. Immune cells, such as macrophages, T cells, B cells, and neutrophils, rely on lipid metabolism for their function, which impacts both innate and adaptive immune responses. Understanding how lipid metabolism influences immune cells is crucial, as it can reveal new therapeutic opportunities for immune-mediated diseases. In this review, we provide a retrospective summary of the research history and milestone events in lipid metabolism research and highlight the importance of lipid metabolism in immune cells. In addition to discussing the various lipid functions, transport, and signaling pathways involved in lipid metabolism, we mainly explore the regulation of immune cell behavior by lipid metabolism, focusing on the roles of lipid metabolites in immune cell proliferation, differentiation, and activation. We further highlight multilevel regulatory mechanisms, including genetic, epigenetic, posttranscriptional, and posttranslational regulation, and their impact on immune cell function. Additionally, we discuss the role of lipid metabolism in diseases such as autoimmune diseases, cancer, neurodegenerative diseases, cardiovascular diseases, aging, and metabolic disorders. Finally, we summarize therapeutic strategies targeting lipid metabolism, the progress of global clinical trials, and future research directions, including lipid-derived biomarkers and innovative therapeutic approaches.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive cancers, typically diagnosed at an advanced stage due to its subtle and often absent early symptoms. Despite representing only 3% of new cancer cases, it is projected to become the second leading cause of cancer-related deaths by 2030. Currently, early diagnosis remains a significant challenge, and survival rates remain poor due to the lack of effective screening tools.

Cancer causes millions of deaths globally every year. At its later stages, cancers are primarily treated with systemic therapies which do not provide an effective cure; the remaining cancer cells ultimately acquire drug resistance, relapse, and metastasize. In particular, polyploid giant cancer cells (PGCCs), which arise in response to diverse cellular stressors such as therapeutic pressure, modulate the tumor microenvironment (TME) and immunity involved in cancer development. However, without the knowledge of well-established signaling cascades targeting PGCCs, the current treatment options for these cells remain limited. This review provides a summary of the latest research associated with PGCC formation and treatment outcomes in common metastatic cancers. In addition, we highlight how some traditional Chinese medicine (TCM) and their bioactive compounds may serve as prospective agents for arresting PGCCs through cell cycle regulation, cell death induction, and TME modulation. Specifically, we identify how these processes are closely associated with the initiation, self-renewal, and termination phases of the PGCC life cycle. Based on the principle in TCM of "strengthening vital qi to eliminate pathogenic factors," the most efficacious herbs for counteracting PGCCs have been identified as Coptis chinensis, Oldenlandia diffusa, Scutellaria baicalensis, Salvia miltiorrhiza, Curcuma longa, Astragali radix, and Panax ginseng. The bioactive compounds of these herbs include berberine, oleanolic acid, wogonin, tanshinone IIA, curcumin, Astragaloside IV, and ginsenoside Rh2. Given the multi-target characteristics of TCM, network pharmacology was performed to allow for an integrative approach to elucidating underlying mechanisms. In particular, TCM administration may modulate both the p53 signaling pathway and cell cycle-related proteins. This, in turn, alleviates PGCC-induced tumor recurrence and resistance. Collectively, this review emphasizes the central role of PGCCs in advanced cancer progression while strengthening the mechanistic insights of TCM in PGCC-oriented therapy.

Polyploid giant cancer cells (PGCCs) are increasingly recognized as contributors to tumor progression, therapeutic resistance, and recurrence. One mechanism behind PGCC formation is cell fusion, a process which is regulated by the canonical Wnt/β-catenin signaling pathway during development and tissue regeneration. This pathway modulates physiological cell fusion events such as myogenesis and placental development, as well as pathological cell fusion between cancer cells or between cancer and stromal or immune cells, contributing to PGCC formation. This review examines the multifaceted roles of the Wnt/β-catenin signaling in cell fusion across developmental and cancer contexts, highlighting its involvement in PGCC biology and outlining how therapeutic targeting of this pathway might help modulate cancer progression.

For glioblastoma (GBM), therapeutic resistance shows a formidable obstacle to effective treatment. Recent insights into cellular plasticity as a novel paradigm for understanding this resistance suggest that tumor cells undergo phenotypic and molecular alterations during GBM progression, collectively termed cellular plasticity. These alterations arise from complex tumor microenvironment (TME) factors, epigenetic changes, and selective pressures induced by radiotherapy or temozolomide (TMZ), ultimately leading to significant tumor heterogeneity and therapeutic resistance. This review will examine the formation of GBM cell plasticity (GCP) and its manipulative mechanisms in therapeutic resistance. GCP arises from the integrated interaction between intrinsic epigenetic and transcriptional reprogramming and extrinsic TME signals, enabling GBM cells to flexibly transition between multiple states. These transitions are not random but constitute an adaptive evolutionary network for therapeutic resistance. We summarize the intrinsic and extrinsic mechanisms driving GCP and promoting the development of therapeutic resistance. Simultaneously, we systematically explore emerging therapeutic strategies targeting GCP, such as inhibiting or reversing GCP by targeting specific signaling pathways. Currently, multiple clinical trials worldwide are underway to improve GBM treatment resistance, spanning cutting-edge fields including targeted therapeutics and immunotherapy. These advances provide crucial directions for developing novel treatment modalities and combination therapies targeting GCP within the context of treatment resistance.

Richter transformation (RT) is a relatively rare but clinically challenging event in the natural history of chronic lymphocytic leukemia (CLL), characterized by the abrupt transformation of CLL into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT is diagnosed through histopathological confirmation, often prompted by clinical signs such as rapid lymph node enlargement, B symptoms, and elevated metabolic activity on PET-CT. Its incidence ranges from 2 % to 10 % over the CLL course, with higher risk in patients harboring specific high-risk (immuno)genetic features. Clonal relationship to the original CLL clone is crucial to understand the biology of the disease and may guide treatment decisions and anticipate RT evolution. Biologically, RT is driven by genomic instability, loss of cell cycle control, MYC activation, NOTCH alterations, and immune evasion mechanisms, including PD-1/PD-L1 upregulation. Transformation timing varies, occurring either early or late in the CLL course, may be preceded by a phase of accelerated disease, and their seeds may be traced back years before their clinical manifestation. Preclinical models, including genetically engineered mice and patient-derived xenografts, have been instrumental in elucidating the molecular underpinnings of RT, assess its interactions with the tumor microenvironment -including through the B-cell receptor-, and offer platforms for testing novel therapeutic strategies. In this review, we will deepen into the biology and evolution of DLBCL-type RT, revisiting recent publications and discussing new avenues for research in this paradigmatic evolution of CLL.

Ultraviolet (UV) radiation-induced melanoma exhibits distinct molecular signatures across genomic, epigenomic, transcriptomic, proteomic, and metabolomic levels that can be identified in blood and other bodily fluids. This presents an opportunity to monitor disease progression with minimal invasiveness. Although considerable biomarker discovery has been observed, only a few biomarkers have been translated into the real world of clinical practice due to analytical variability, insufficient validation, and questionable clinical utility. This review critically evaluates multi-omic biomarkers of UV-induced melanoma in the context of clinical chemistry and diagnostic laboratory medicine, emphasizing robust analytical qualities, pre-analytical standardization, and clinical validation. Circulating tumor DNA (ctDNA) enables the quantitative tracking of BRAF, NRAS, and TERT mutations using droplet digital PCR (ddPCR) and next-generation sequencing (NGS). Longitudinal ctDNA dynamics show 85-92% concordance with tissue genotypes in advanced disease and may anticipate radiographic progression. RASSF1A methylation is an epigenetic biomarker, and a combination of multi-markers may outperform a single-analyte solution. Reproducible diagnostic and prognostic stratification of circulating miRNA signatures, such as MEL38, can be used at different stages of the disease, although careful control is essential to circumvent hemolysis and normalization issues in the blood samples. Protein biomarkers, including S100B, C-reactive protein, and dynamic interleukin-8 levels, have been investigated for prognostication and therapy monitoring in targeted and immunotherapy. Metabolomic profiling has revealed signatures of treatment response, with a substantial proportion of metabolites demonstrating acceptable interlaboratory reproducibility under standardized protocols. Pre-analytical confounders (blood collection tubes, hemolysis, storage conditions), platform-dependent analytical variation, lack of external quality assessment programs, and scarcity of demonstrations of clinical utility in prospective biomarker-directed research are critical translational barriers. Such standardized handling of specimens, commutable reference materials, and reporting of the characteristics of analytical performance would be clearly linked to effective clinical use in accordance with the requirements of laboratory medicine.