Onco

Background: Small cell carcinoma of the bladder (SCCB) is a rare, aggressive malignancy with no established standard of care for metastatic disease. The prognosis is dismal; median survival ranges from 12 to 20 months, and long-term survival is exceptional. Case Presentation: We present a 67-year-old man diagnosed in 2018 with metastatic SCCB involving the liver, bone, and ureter. He achieved a complete metabolic response following six cycles of cisplatin–etoposide, followed by consolidative pelvic radiotherapy with a bladder boost. Upon disease progression in 2019, molecular profiling identified a high tumour mutational burden (19.9 mut/Mb), PD-L1 CPS > 1%, and multiple genomic alterations (including MDM2, RAD51D, and TERT). Dual immune checkpoint inhibition (ICI) with ipilimumab and nivolumab was initiated. Although treatment was interrupted and subsequently discontinued due to grade 3 immune-related adverse events, including hepatitis and pneumonitis, the patient maintained a sustained remission off therapy. In January 2025, nearly seven years post-diagnosis, he developed a solitary frontal brain metastasis. He underwent resection and adjuvant stereotactic radiosurgery, achieving local control. He remains under surveillance with no evidence of extracranial recurrence. Conclusions: This case illustrates one of the longest reported survivals in metastatic SCCB. It highlights the utility of molecular profiling in guiding salvage therapy and the potential for durable ICI responses even after discontinuation due to toxicity. Furthermore, late recurrence in the brain emphasizes the central nervous system’s role as a sanctuary site, necessitating prolonged vigilance. Full article

PROTACs represent a cutting-edge approach to the discovery of innovative cancer therapies. By exploiting the cell’s ubiquitin–proteasome system, PROTACs induce the selective degradation of target proteins, providing a distinct advantage over conventional inhibitors that only block protein function. This review delves into the design principles and mechanisms underlying PROTACs, emphasizing their potential to circumvent drug resistance and achieve prolonged therapeutic effects. Recent advancements have focused on enhancing the specificity, bioavailability, and overall efficacy of PROTACs, demonstrating promising results in preclinical cancer models. The ability of PROTACs to target previously “undruggable” proteins opens new avenues for cancer treatment, offering the potential for more effective and personalized therapeutic strategies. As research continues to evolve, the optimization and clinical translation of PROTACs could declare a new era in oncology, revolutionizing the landscape of cancer drug discovery and personalized medicine. Full article

The intestinal microbiome has emerged as a clinically significant modulator of outcomes across multiple domains of cancer care. In hematopoietic stem cell transplantation (HSCT), loss of microbial diversity and depletion of short-chain fatty acid-producing commensals are independently associated with graft-versus-host disease (GvHD), bloodstream infections, transplant-related mortality, and overall survival. Mechanistic studies have identified interconnected pathways—including butyrate-mediated epithelial protection, tryptophan-derived aryl hydrocarbon receptor signaling, bile acid metabolism, and Paneth cell–intestinal stem cell interactions—through which microbial communities regulate intestinal barrier integrity and immune homeostasis. These insights have provided the biological rationale for therapeutic strategies aimed at restoring microbial ecology. Fecal microbiota transplantation (FMT) has demonstrated promising clinical activity in steroid-refractory acute GvHD, with one meta-analysis reporting a pooled clinical remission rate of 64% (95% CI, 51–77%) across prospective single-arm studies, and proprietary live biotherapeutic products (LBPs) such as MaaT013 met the primary endpoint of the single-arm phase III ARES trial, achieving a day-28 gastrointestinal overall response rate of 62%; however, the CHMP adopted a negative opinion on its conditional marketing authorization application in June 2026, citing limitations of the single-arm design, and a re-examination is pending. In parallel, gut microbiome composition has been associated with immune checkpoint inhibitor (ICI) response, and early-phase FMT studies suggest that microbiome modulation may restore sensitivity to anti-PD-1 therapy in some patients with refractory melanoma and may enhance treatment responses in first-line ICI settings; however, these findings derive primarily from small, uncontrolled or early-phase studies. Defined single-strain approaches, notably Clostridium butyricum MIYAIRI 588 (CBM588), have shown encouraging secondary clinical efficacy signals in two small, randomized phase I trials in metastatic renal cell carcinoma, including significantly prolonged progression-free survival in one trial and a higher objective response rate in another; however, neither trial met its prespecified primary microbiome endpoint of increased Bifidobacterium spp. abundance. Emerging evidence further links antibiotic-induced dysbiosis to impaired chimeric antigen receptor T-cell (CAR-T) therapy outcomes, while short-chain fatty acids have been identified as direct enhancers of CAR-T cell effector function. This review synthesizes the current evidence for microbiome-based therapeutics across HSCT, GvHD, ICI therapy, CAR-T cell therapy, and infection prevention, and addresses cross-cutting translational challenges including antibiotic stewardship, donor selection, safety in immunocompromised populations, and pharmacomicrobiomics. While randomized controlled trial data remain limited and many approaches are investigational, the convergence of mechanistic, observational, and early interventional evidence positions microbiome restoration as a promising frontier in precision oncology. Full article

Tumour hypoxia significantly influences disease advancement and treatment resistance in oral squamous cell carcinoma (OSCC). Hypoxia-inducible factor-1α (HIF-1α) is preserved when oxygen is lacking and triggers the expression of hypoxia-responsive genes that have roles in angiogenesis, metabolic adaptability, tumour cell viability, invasion, and metastasis. The elevated levels of vascular endothelial growth factor (VEGF) induced by HIF-1α result in atypical angiogenesis. The dysfunction of cell junction proteins and heightened activity of matrix metalloproteinases caused by hypoxia facilitate cancer invasion and metastasis. Hypoxic stress prompts cellular modifications, including autophagy and the preservation of cancer cell populations with enhanced survival capabilities, hence facilitating tumour recurrence and heterogeneity. Hypoxia diminishes the effectiveness of standard chemotherapy and radiotherapy due to decreased drug transport, hindered cell growth, and diminished oxygen-dependent radiation-induced DNA damage. Thus, treatment strategies for the hypoxic tumour microenvironment encompass the suppression of HIF and VEGF, tumour reoxygenation, hypoxia radiosensitizers, and hypoxia-activated lethal compounds. Nonetheless, the diverse and fluctuating characteristics of tumour hypoxia, along with the initiation of compensatory survival mechanisms, continue to pose significant obstacles. Enhanced comprehension of hypoxia-induced molecular networks and the advancement of multimodal, biomarker-directed treatment strategies could improve outcomes in OSCC. Full article

Prolactin (PRL) is a hormone synthesized by lactotrophs in the anterior pituitary gland. It is also produced by extrapituitary glands such as the prostate and breast, where it promotes growth. Notably, PRL also contributes to cancer development in these glands. PRL is known to stimulate cancer cell migration, suggesting its possible involvement in metastasis, for which cell migration is a critical step. However, the role and mechanisms by which PRL induces cancer cell migration are not yet fully understood. One well-studied mechanism involves its receptor, the prolactin receptor (PRLR). After PRL binds to its receptor, PRLR dimerizes and induces transphosphorylation of Janus kinase 2 (JAK2), which subsequently phosphorylates p21-activated kinase 1 (PAK1), leading to increased cell migration. Although the PRL-JAK2-PAK1 pathway in cancer cell migration has been investigated, the molecular mechanism remains incompletely understood. Additionally, other PRL-activated pathways are implicated in migration, but their roles remain debated. This narrative review examines and discusses the main findings on the involvement of PRL in the migration of cancerous and non-cancerous cells, as well as the molecular mechanisms involved. We conclude that PRL promotes the migration of both cancerous and non-cancerous cell lines and should, therefore, be taken into account in future cancer research. Full article

Medulloblastoma is increasingly best understood not simply as a cell-autonomous embryonal tumour, but as a family of molecularly and anatomically distinct diseases shaped by the developing cerebellum and posterior fossa. The four principal molecular subgroups—WNT, sonic hedgehog, Group 3 and Group 4—differ not only in genetics and outcome, but also in barrier permeability, immune composition, stromal crosstalk and routes of dissemination. Histopathological variation likewise reflects differences in tumour architecture, neuronal maturation and cytological aggressiveness that intersect with, but are not reducible to, molecular subgroup. This review takes a microenvironment-centred view of medulloblastoma biology. It asks how non-malignant cells, fluid compartments and physical interfaces—including immune cells, the choroid plexus and cerebrospinal fluid, the blood–brain and blood–tumour barriers, astrocytes and experimental model systems—modify tumour initiation, progression, therapy response and relapse. The central argument is that the medulloblastoma tumour microenvironment is not merely sparse or passive; instead, pathological, spatial and molecular analyses of human tumours, complemented by models that preserve the relevant niche, reveal a developmentally patterned, subgroup-specific and therapeutically tractable ecosystem. Full article

Background/Objectives: Prostate cancer is biologically heterogeneous, and prognostic stratification informs the choice between definitive treatment and conservative management. Most evidence on the Gleason score addresses prostate cancer-specific mortality rather than survival from any cause. We assessed the association between Gleason score category and overall survival in a contemporary population-based cohort. Methods: Using Surveillance, Epidemiology, and End Results (SEER) Research Data from 17 registries (November 2024 submission), we included men aged 40 years and older with a first primary malignant prostate cancer and a recorded Gleason Score Clinical Recode (2010+). Because this recode is undefined before 2010, the analytic period was 2010–2019. Gleason score was categorized as ≤6, 7, and ≥8. Overall survival was estimated by Kaplan–Meier methods and compared by log-rank test; multivariable Cox regression adjusted for age, race and ethnicity, marital status, summary stage, surgery at the primary site, radiation therapy, and chemotherapy, with localized disease as the stage reference. Results: Among 374,763 men, 145,668 (38.9%) had Gleason ≤ 6, 148,773 (39.7%) Gleason 7, and 80,322 (21.4%) Gleason ≥ 8, with mortality during follow-up of 11.3%, 14.6% and 36.6% respectively (log-rank p < 0.0001). Adjusted hazards of death were higher for Gleason 7 (HR 1.53, 95% CI 1.50–1.57) and Gleason ≥ 8 (HR 2.89, 95% CI 2.82–2.95) relative to Gleason ≤ 6. Advancing age, regional disease (HR 1.47, 95% CI 1.43–1.51) and distant disease (HR 3.74, 95% CI 3.65–3.84) were also associated with increased mortality. The grade association attenuated over follow-up, the hazard ratio for Gleason ≥ 8 falling from 4.12 within two years to 2.17 beyond five years. Conclusions: Gleason score category is independently associated with overall survival and retains prognostic value on the all-cause mortality scale, with greatest discrimination in the years immediately following diagnosis. Full article

(1) Background: Modifications to tumor classifications could fundamentally alter the foundation of research approaches. A concrete illustration of this issue is the actual WHO classification of tumors of the central nervous system, published in 2021. According to the WHO classification, GBM is an IDH wild-type tumor. However, some multi-omics databases retain the classification from the time the samples for the datasets were collected, prior to the WHO 2021 classification, including IDH mutant GBMs. We were interested in assessing the number of papers published in the biomedical literature from 2022 to 2025 that are based on these databases, to ensure the correct implementation of the WHO 2021 classification of GBM. (2) Methods: We systematically reviewed publications in the biomedical literature from 2022 to 2025 that utilized the two most widely used multi-omics databases in the glioma research field, the CGGA and TCGA databases, to assess the correct application of the classification of GBM. (3) Results: We identified 269 publications, but only 45 (14%) correctly included only IDH wild-type GBM; 83 (33%) also contained IDH mutant tumors; and 141 (53%) provided no information about the IDH status of their research material. (4) Conclusions: Using a systematic search strategy, we found that 1/3 of published papers used IDH mutant tumors, and 1/2 of the studies did not report the IDH status of the tumors. Full article

Epigenetic mechanisms play a crucial role in OC drug resistance, and emerging evidence suggests that dysregulated epigenetic modifications are among the key contributors to OC. Epigenetic agents, including DNA methyltransferase inhibitors, histone deacetylase inhibitors, and non-coding RNA-based therapeutics, have important limitations, including poor water solubility, limited tissue distribution, low stability, and systemic toxicity. To overcome this, a novel drug delivery system is needed to manage variability in drug administration and maximize the efficacy of these drugs. In this regard, nanotechnology offers an attractive option for formulating epigenetic drugs with various encapsulation strategies to increase bioavailability and drug efficacy, reduce drug dose, administration frequency, and toxicity, and enhance cellular internalization and tumor-targeted delivery. In this review, we summarize various epigenetic regulators and their roles in OC therapy resistance as well as the development of nanosystems for epigenetic drug delivery, which could lay the foundation for designing nanoformulations encapsulating epigenetic therapeutics, ultimately advancing personalized, targeted therapy for patients with OC. This review also discusses the current clinical status of nanocarrier platforms and translational barriers that limit the clinical development of epigenetic nanomedicine, highlighting the future directions required for successful clinical translation. Full article

Cancer metastasis is the leading cause of cancer-related mortality, accounting for more than 90% of cancer deaths worldwide. However, the epigenetic mechanisms governing the metastatic cascade remain incompletely understood. Epigenetic reprogramming, including reversible changes in histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA (ncRNA)-mediated regulation, enables tumor cells to acquire invasive, migratory, stem-like, and immune-evasive characteristics. During epithelial-to-mesenchymal transition (EMT), key epigenetic regulators such as histone deacetylases (HDACs), the Polycomb repressive complex 2 (PRC2) subunit EZH2, lysine-specific demethylase 1 (LSD1/KDM1A), and bromodomain and extraterminal (BET) proteins repress epithelial gene expression while activating mesenchymal transcriptional programs, promoting invasion and dissemination. At distant sites, epigenetic plasticity facilitates metastatic colonization through mesenchymal-to-epithelial transition (MET) and adaptive chromatin remodeling. Because these changes are reversible, they represent attractive therapeutic targets. HDAC, EZH2, LSD1/KDM1A, BET, and DNA methyltransferase (DNMT) inhibitors have shown promise in preclinical models of metastasis, with several advancing through clinical trials. Long non-coding RNAs, particularly HOTAIR, function as epigenetic scaffolds that reinforce metastatic programs, while reciprocal interactions between tumor cells and the tumor microenvironment (TME) drive epigenetic adaptations that promote immune evasion and metastatic progression. In addition, circulating tumor DNA (ctDNA) methylation signatures are emerging as minimally invasive biomarkers for assessing metastatic risk and monitoring treatment. This review summarizes current insights into the epigenetic regulation of cancer metastasis, evaluates emerging epigenetic therapies, and highlights translational opportunities to advance precision anti-metastatic strategies and improve patient outcomes. Full article

Background/Objectives: Cutaneous adverse events (cAEs) are among the most common toxicities associated with modern anticancer therapies and can significantly affect quality of life, treatment adherence, and therapeutic outcomes. This narrative review aims to provide an updated overview of the mechanisms, clinical manifestations, prognostic implications, and management strategies of cancer therapy-related cutaneous toxicities, with a particular focus on precision oncodermatology. Methods: A narrative review of the recent literature was performed, integrating evidence from clinical studies, meta-analyses, pharmacovigilance investigations, consensus guidelines, and translational research. The review examines cutaneous toxicities associated with immune checkpoint inhibitors, targeted therapies, antibody–drug conjugates, and other emerging anticancer treatments. Results: Four major axes were identified: immune disinhibition, epithelial signaling inhibition, cytotoxic epithelial injury, and cytokine-driven immune activation. Cutaneous immune-related adverse events (cirAEs) emerged as potential biomarkers of treatment efficacy, particularly vitiligo, lichenoid, and psoriasiform eruptions. Increasing evidence supports the use of steroid-sparing biologic therapies, including dupilumab, omalizumab, anti-IL-17 agents, and Janus kinase inhibitors, although prospective validation remains limited. Recent advances in immunologic endotyping have identified distinct inflammatory pathways that may enable personalized therapeutic approaches. Antibody–drug conjugates represent an expanding source of unique dermatologic toxicities requiring dedicated management strategies. Emerging biomarkers, including cytokine signatures and microRNAs, may further refine risk stratification and treatment selection. Conclusions: The management of cancer therapy-related cutaneous toxicities is evolving toward a precision medicine model integrating clinical phenotype, immunologic endotype, and biomarker profiling. Early multidisciplinary intervention and mechanism-based therapeutic strategies may improve patient outcomes while preserving anticancer efficacy. Prospective studies are needed to validate biomarker-guided and steroid-sparing approaches in oncodermatology. Full article

Background/Objectives: Primary renal NETs are exceptionally rare neoplasms that occur disproportionately in horseshoe kidneys. Their rarity and non-specific clinical and radiological features make preoperative diagnosis particularly challenging. Methods: Herein, we report the case of a 60-year-old woman presenting with a painful left lumbar mass associated with dysuria and pollakiuria. Results: Computed tomography revealed a large heterogeneous tumor arising from the left moiety of a horseshoe kidney. Histopathological examination of the resected specimen demonstrated a 14 cm well-differentiated NET (grade 1) with diffuse chromogranin A and synaptophysin expression, a mitotic count of 1 per 2 mm², and a Ki-67 proliferation index of <1%. The histopathological and immunohistochemical findings, together with the absence of an extrarenal primary site on staging investigations, supported the diagnosis of a primary renal NET. The postoperative course was uneventful, and the patient remained disease-free after two years of follow-up. Conclusions: This case highlights the diagnostic challenges posed by this rare entity and underscores the importance of including primary renal neuroendocrine tumors in the differential diagnosis of renal masses arising in horseshoe kidneys. Full article

Head and neck squamous cell carcinoma (HNSCC) remains a significant global health burden with limited survival improvement in locally advanced disease despite multimodal therapy. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have demonstrated substantial clinical benefit in recurrent or metastatic HNSCC, establishing PD-1 blockade as a standard of care. Similar approaches in locally advanced disease, including concurrent administration with chemoradiotherapy or use in the adjuvant setting, have not demonstrated improvement in survival outcomes across multiple randomized trials. Perioperative strategies incorporating neoadjuvant and adjuvant checkpoint inhibition have shown improved event-free and disease-free survival in resectable disease. Meta-analyses of concurrent and adjuvant approaches confirm limited benefit in unselected populations, with modest improvements restricted to biologically defined subgroups. Trial outcomes across disease settings demonstrate a consistent pattern in which therapeutic efficacy varies despite the use of similar agents. Rather than simply summarizing these clinical findings, this review integrates evidence across recurrent/metatstatic, unresected locally advanced and perioperative disease settings into a biologically focused framework to help explain the varying efficacies of immune checkpoint inhibition in HNSCC. Current evidence indicates that the effectiveness of immunotherapy in HNSCC is determined by the biologic context of treatment, including tumor antigen availability, host immune competence, and timing of immune activation. Administration of checkpoint blockade in the presence of intact tumor antigen and preserved immune function is associated with improved outcomes, whereas treatment delivered during or after cytotoxic therapy is limited by lymphopenia and reduced antigen exposure. By synthesizing randomized clinical evidence through this biologic framework, the review provides a conceptual perspective that may help explain previous trial outcomes and inform future biomarker-driven patient selection and treatment sequencing. Optimization of immunotherapy in HNSCC will depend on the integration of immune activation with disease context rather than an escalation of therapeutic intensity. Full article

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, accounting for 15% of lung cancer cases worldwide. In recent years, the histological transformation from non-small-cell lung cancer (NSCLC) to SCLC has become a significant mechanism of acquired resistance, especially in patients undergoing treatment with tyrosine kinase inhibitors (TKIs) or immunotherapy. Although there is growing clinical understanding, the crucial biological mechanisms that drive this phenotypic switch are still not fully understood. Transformed SCLC (T-SCLC) seems to exhibit differences from de novo SCLC regarding molecular characteristics and tumor microenvironment, indicating unique evolutionary paths. While traditional chemotherapy has been the main treatment method after transformation, patient outcomes continue to be unsatisfactory, highlighting the necessity for a more profound mechanistic insight and the development of more effective treatments. Full article

Background/Objectives: Irinotecan is a key late-line agent in metastatic gastric cancer, but its dose-limiting toxicities—severe neutropenia and diarrhea—are strongly influenced by UGT1A1 promoter polymorphisms. Commercial genotyping kits in Japan routinely interrogate only the common *6 and *28 alleles and may fail to resolve rarer TATA-box variants. We report a case in which an indeterminate commercial result unmasked an extremely rare loss-of-function genotype. Methods: A Japanese man in his 60s with HER2-negative, microsatellite-stable metastatic gastric cancer progressing after four prior lines underwent pretreatment UGT1A1 genotyping with a commercial DNA chip in anticipation of irinotecan. When the *28 result returned as indeterminate owing to a TA-ratio error, reflex Sanger sequencing of the UGT1A1 promoter TATA box was performed. Results: The chip reported *6 as wild-type but could not resolve *28. Sanger sequencing identified one allele with seven TA repeats (*28) and one with eight TA repeats (*37), with no wild-type six-repeat allele—a *28/*37 compound heterozygote. The *37 allele is exceptionally rare in Japanese individuals (ToMMo 61KJPN allele frequency 0.000294) and has historically been reported almost exclusively in individuals of African ancestry. This genotype has previously caused fatal neutropenic colitis despite preemptive dose reduction. Given the patient’s frailty and limited expected benefit, irinotecan was withheld entirely. Conclusions: Indeterminate commercial UGT1A1 results may conceal rare loss-of-function alleles with divergent functional consequences. Such results should trigger confirmatory sequencing rather than empiric dose reduction, and institutions should establish reflex pathways in advance to support biomarker-informed, frailty-adapted treatment selection. Full article

Cancer is a leading health issue worldwide, affecting approximately 20 million people annually. Developing efficient chemotherapy agents for cancer treatment is a challenging, costly, and time-consuming process. Drug repurposing for cancer treatment provides an optimal alternative, as the pharmacokinetic properties and the safety of these drugs have been previously tested. It also offers a faster and more cost-effective path to novel cancer therapies, which is especially valuable when conventional treatments face resistance or toxicity limitations. Antipsychotic drugs, which are primarily used for treating psychiatric disorders, including schizophrenia and bipolar disorder, have recently been investigated for their potential anticancer effects through drug repurposing strategies. While covering preliminary data and providing an overview of their mechanisms of action, this review highlights the latest research on antipsychotic medications’ emerging potential in oncology in experimental models, emphasizing their observed anticancer effects in preclinical studies, safety profile and capacity to enhance the effectiveness of conventional therapies. Despite growing interest, a research gap remains in translating these findings to clinical oncology, an issue this review addresses by proposing future investigative directions. Full article

(1) Background: Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies due to late diagnosis, aggressive tumor biology, and limited therapeutic options. Artificial intelligence has emerged as a promising tool to improve detection, risk stratification, and treatment planning. This study aims to review the current clinical applications of artificial intelligence in the management of pancreatic cancer and evaluate its translational potential. (2) Methods: A comprehensive literature search was conducted across major databases (PubMed/MEDLINE, Scopus, Web of science and Cochrane) for studies published between 2015 and 2026. Eligible studies included clinical investigations and systematic reviews reporting quantifiable outcomes related to diagnosis, staging, prognostication, and treatment response using artificial intelligence methods. (3) Results: A total of 24 studies were included, most of which were retrospective and utilized imaging, histopathology, and clinical datasets. Artificial intelligence demonstrated high diagnostic performance, particularly in imaging-based detection and lesion characterization, with several models achieving excellent accuracy. Applications in staging, surgical planning, and prognostication also showed promising results, although external validation and prospective data were limited. (4) Conclusions: Artificial intelligence has significant potential to enhance the management of pancreatic cancer, particularly as a decision-support tool. However, further prospective validation and integration into clinical workflows are required before widespread adoption. Full article

Genomic instability is a defining feature of cancer progression and therapeutic resistance, yet contemporary oncology interprets it largely through tumor-intrinsic genetic alterations, with less attention to the evolving host physiological context in which DNA damage accumulates and genome maintenance operates. In this perspective, we propose a longitudinal host-transfer-state framework that treats host physiology not as a static background but as a continuously evolving adaptive system. Gut microbial ecology, micronutrient physiology, inflammatory signaling, circadian organization, hydration, environmental exposures, and chronic stress are framed as interacting biologic transfer systems that shape DNA repair fidelity, oxidative buffering, immune coordination, and adaptive tumor behavior over time. These influences are proposed to vary by tumor type, treatment context, and individual physiologic reserve, and clinically observable disease may lag behind deeper latent biologic dynamics. We further outline how longitudinal multi-omic integration and constrained, bounded artificial intelligence—used for longitudinal data integration, normalization, contextualization, and bounded analytical support rather than autonomous decision-making—could identify patient-specific constraints on genome maintenance and treatment tolerance. Host-directed strategies are presented as complementary to, not replacements for, established tumor-directed therapies. Full article

Obesity is increasingly recognized as a complex systemic disorder rather than a simple consequence of excess energy intake and fat accumulation. This review presents a systems biology framework that examines how obesity-driven disruption of inter-organ communication networks contributes to chronic disease susceptibility, with particular emphasis on colorectal cancer (CRC). Disrupted signaling among the brain, adipose tissue, liver, skeletal muscle, gut, and immune system generates maladaptive feedback loops that promote chronic metabolic inflammation (metaflammation), loss of physiological resilience, and progressive metabolic dysfunction. Within this framework, obesity is redefined as a network disease characterized by neuroendocrine dysregulation, adipose tissue remodeling, immune dysfunction, impaired organ crosstalk, and alterations in the gut microbiome. A central feature of this dysregulation is persistent low-grade inflammation driven by immune-metabolic reprogramming and sustained activation of inflammatory pathways. Obesity-associated metaflammation is further linked to accelerated biological aging through mechanisms involving cellular senescence, mitochondrial dysfunction, oxidative stress, and impaired metabolic resilience. These interconnected processes create a tumor-promoting environment by enhancing oncogenic signaling, disrupting intestinal barrier integrity, altering microbial and metabolic signaling, impairing immune surveillance, and promoting epithelial dysfunction, thereby increasing susceptibility to CRC. The review also examines how behavioral, circadian, environmental, and socioeconomic factors influence metabolic health and cancer risk. Finally, emerging translational opportunities, including biomarker-guided risk stratification, precision prevention, metabolic network restoration, and integrative lifestyle and pharmacological interventions, are discussed. Collectively, this review reframes obesity as a whole-body regulatory disorder and provides an integrated conceptual framework linking metabolism, inflammation, aging, and colorectal carcinogenesis to inform future prevention and therapeutic strategies. Full article