Search Results (11,956)

Breast cancer remains one of the leading causes of global mortality, which has growing driving interest in dietary natural products for potential chemopreventive and complementary approaches. Cherries (Prunus species) are rich in bioactive phytochemicals, notably anthocyanins, hydroxycinnamic acids, and the flavonols quercetin and kaempferol. This review aims to examine and discuss current research on the molecular targets and mechanisms of action of whole cherry extracts and their primary flavonols quercetin and kaempferol across various breast cancer subtypes. Preclinical studies indicate that these compounds exert multi-targeted effects by inducing apoptosis, inhibiting cell proliferation, and suppressing metastatic pathways. Additionally, these flavonols show potential in reversing multidrug resistance. A whole-food approach highlights the candidate synergistic properties of these phytochemical complexes, but low oral bioavailability and rapid metabolism severely limit their clinical translation. Therefore, utilizing innovative drug delivery systems remains crucial to improving their stability, absorption, and overall therapeutic efficacy. Full article

Bufalin is a naturally occurring bufadienolide with broad-spectrum anticancer activity. Unlike conventional cytotoxic agents, bufalin exerts pleiotropic antitumour effects by directly modulating oncogenic proteins and promoting their degradation. It also disrupts metabolic plasticity, induces multiple forms of regulated cell death, counteracts therapeutic resistance, and remodels the immunosuppressive tumour microenvironment. However, the further application of bufalin is hindered by poor aqueous solubility, rapid systemic clearance, a narrow therapeutic window, and dose-limiting toxicity. Nanodrug delivery systems (NDDSs) offer a promising strategy for translating these interconnected pharmacological effects into spatially and temporally controlled therapeutic responses. This review summarises the distinctive anticancer mechanisms of bufalin and systematically evaluates the organic, inorganic, biomimetic, and hybrid nanocarriers developed for its delivery. Particular attention is given to tumour-responsive drug release, the targeting of cancer stem cells, the induction of ferroptosis and pyroptosis, metabolic modulation, sensitisation to phototherapy, and the activation of antitumour immunity. Finally, the major translational challenges are critically examined to inform the further rational development of bufalin-based nanomedicines. Full article

Cirsium japonicum is a medicinal plant traditionally used in East Asian medicine and contains multiple bioactive constituents with potential anticancer properties. This review critically evaluates the anticancer effects of C. japonicum and its associated constituents within the Hallmarks of Cancer framework. Evidence was classified as direct plant-specific evidence, constituent-based evidence, or contextual mechanistic evidence to distinguish findings obtained using botanical preparations from those generated using purified compounds derived from other sources. Direct studies of C. japonicum extracts, flavonoid fractions, phenylpropanoid glycosides, and C. japonicum var. maackii-mediated gold nanoparticles demonstrate antitumor, cytotoxic, antiangiogenic, immunomodulatory, and ferroptosis-associated activities, although target-level validation remains limited. Among its associated constituents, pectolinarigenin has the most developed mechanistic evidence, involving RRM2–CDK1, TOP2A, STAT3, and PI3K/AKT/mTOR signaling. Apigenin, luteolin, acacetin, linarin, cirsimaritin, and pectolinarin additionally influence regulated cell death, proliferative signaling, angiogenesis, metastasis, immune regulation, metabolic vulnerability, senescence, and therapy response. However, much of this evidence relies on pathway-associated changes rather than direct target engagement or genetic validation. Furthermore, the pharmacokinetics, systemic exposure, botanical standardization, tumor selectivity, and clinical relevance of these compounds remain insufficiently characterized. Future studies should prioritize standardized preparations, quantitative exposure analysis, functional target validation, clinically relevant models, and carefully designed combination strategies. Collectively, C. japonicum provides a promising multi-hallmark framework for anticancer investigation, but substantial translational evidence is still required before its therapeutic potential can be established. Full article

Colorectal cancer (CRC) exhibits substantial metabolic heterogeneity, but the organization of sphingolipid remodeling remains incompletely understood. In this exploratory single-center study, we integrated patient-matched tissue lipidomics, systemic oxidative stress profiling, and independent transcriptomic analyses. Tumor tissue, adjacent non-neoplastic mucosa, and preoperative serum were collected from 40 patients with CRC, with serum obtained from 23 hospitalized non-cancer controls. Sphingolipids were quantified by UHPLC–MS/MS, while total antioxidant capacity, total oxidant status, and oxidative stress index characterized systemic redox status. Paired lipidomics revealed coordinated remodeling with increased S1P-associated measures, selective ceramide depletion, and elevated S1P-to-ceramide ratios. Multivariate analyses did not identify stable discrete lipidomic subgroups and revealed variation consistent with a continuum-like organization within the measured sphingolipid feature space. In separate principal component analyses, ratio-derived variables showed a more concentrated low-dimensional covariance structure than absolute lipid concentrations. Circulating sphingolipids showed limited correspondence with tumor-local remodeling, whereas oxidative stress markers showed strong apparent discrimination between CRC and hospitalized non-cancer controls, although this finding may be affected by residual confounding. TCGA–GTEx analyses provided complementary pathway-level transcriptomic context, while anatomically resolved analysis of 374 TCGA tumors identified 3376 genes significantly associated with colorectal anatomical position, including six sphingolipid-related genes. Overall, these exploratory findings support a conceptual CRC Metabolic Continuum while requiring validation in larger, independent cohorts. Full article

Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide, with limited improvements in long-term survival despite significant progress in systemic therapy. This review focuses predominantly on pancreatic ductal adenocarcinoma (PDAC), the most common and best-studied pancreatic malignancy, while referencing other pancreatic neoplasms only where directly relevant to intrapancreatic fat biology. Obesity has emerged as a major modifiable risk factor for PDAC. In addition, increasing attention has focused on ectopic fat depots, particularly intrapancreatic fat, as potential mediators linking metabolic disease to pancreatic carcinogenesis. This narrative review summarizes the classification and epidemiology of PDAC, the relationship between obesity and pancreatic cancer risk, the biology of intrapancreatic fat, as well as putative mechanisms by which intrapancreatic fat may promote pancreatic carcinogenesis. In addition, we will review current diagnostic approaches, therapeutic and preventive considerations, and key unanswered questions for future research on the relevance of intrapancreatic fat deposits. Collectively, available evidence supports intrapancreatic fat as a biologically plausible and potential mediator of pancreatic cancer risk, warranting further prospective investigation. Full article

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming and mitochondrial dysfunction, yet the molecular regulators underlying these alterations remain incompletely understood. AarF domain-containing kinase 1 (ADCK1) is an evolutionarily conserved protein associated with mitochondrial function, but its role in HCC bioenergetics has not been defined. In this study, we investigated the effects of ADCK1 on mitochondrial metabolism using CRISPR/Cas9-mediated ADCK1 knockout in HepG2 and SNU-449 HCC cells. Mitochondrial respiration, glycolytic activity, ATP production, lactate generation, mitochondrial membrane potential, and superoxide production were assessed following ADCK1 KO. ADCK1 KO resulted in marked reductions in basal and maximal mitochondrial respiration, ATP-linked respiration, glycolytic activity, intracellular ATP, and lactate production in both HCC cell models. ADCK1 KO also reduced mitochondrial membrane potential in a clone-dependent manner. Despite these profound bioenergetic defects, mitochondrial superoxide production was not consistently altered across the knockout clones. These findings indicate that ADCK1 supports both oxidative phosphorylation and glycolytic metabolism and is required for maintenance of bioenergetic homeostasis in HCC cells. Collectively, our results identify ADCK1 as a previously unrecognized regulator of HCC mitochondrial metabolism. Full article

Background: The Lung Immune Prognostic Index (LIPI), based on the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase, may reflect systemic inflammation and tumor-related metabolic burden. This study evaluated the prognostic value of pretreatment LIPI and its relationship with programmed death-ligand 1 (PD-L1) expression in patients with advanced non-small cell lung cancer (NSCLC) receiving nivolumab after first-line therapy. Methods: A total of 158 patients were included in this retrospective, single-center study. Patients were classified into LIPI 0, LIPI 1, or LIPI 2 groups according to their pretreatment LIPI scores. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analysis and multivariable Cox regression. The prognostic value of LIPI was also evaluated within PD-L1-negative and PD-L1-positive subgroups, and LIPI × PD-L1 interactions were explored. Harrell’s concordance index was used to examine whether adding LIPI improved model discrimination beyond clinical variables and PD-L1 expression. PD-L1 data were available for 145 patients. Results: Median PFS was 566, 340, and 109 days for the LIPI 0, LIPI 1, and LIPI 2 groups, respectively, while median OS was 841, 760, and 201 days, respectively; the differences were statistically significant for both outcomes (both p < 0.001). The objective response rate (ORR) was 55.6%, 36.5%, and 4.9%, whereas the disease control rate (DCR) was 75.9%, 65.1%, and 14.6% in the LIPI 0, LIPI 1, and LIPI 2 groups, respectively (both p < 0.001). In multivariable analyses, higher LIPI remained independently associated with shorter PFS and OS, with the strongest association observed in the LIPI 2 group. LIPI also differentiated survival outcomes within both PD-L1-negative and PD-L1-positive subgroups, although no significant LIPI × PD-L1 interaction was identified for PFS or OS. The addition of LIPI increased the C-index from 0.583 to 0.698 for PFS (ΔC-index, 0.115; p < 0.001) and from 0.588 to 0.697 for OS (ΔC-index, 0.109; p = 0.003). Conclusions: Pretreatment LIPI was independently associated with PFS and OS in patients with advanced NSCLC receiving nivolumab after first-line therapy. Its association remained after adjustment for available PD-L1 expression data, and its addition improved model discrimination. These findings suggest that LIPI may provide prognostic information complementary to PD-L1 expression and routinely available clinical factors. Full article

Background: Prostate cancer (PC) is a heterogeneous disease in which the histopathological grade does not always reflect underlying biological behavior. While transcriptomic studies have provided insight into tumor biology, grade-associated molecular changes remain incompletely defined, particularly in underrepresented populations such as those from the Middle East and North Africa (MENA) region. Methods: In this study, we used a pathology-guided transcriptomic approach to examine gene expression patterns across PC grades in a MENA cohort. RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tissues, including benign prostatic hyperplasia (BPH, n = 7), low-grade tumors (Gleason 6–7 [3 + 4]; LG; n = 7), and high-grade tumors (Gleason 7 [4 + 3]–10; HG; n = 7). Differential expressions, pathway-level enrichment analyses and the estimation of immune cell composition were carried out, followed by comparison with publicly available datasets (TCGA-PRAD, n = 496), including LG tumors (n = 292) and HG tumors (n = 204), using the GEPIA2 and UALCAN platforms. Selected genes were further assessed using qRT-PCR in an independent set of samples (n = 21). Representative immunohistochemical images from the Human Protein Atlas were reviewed to provide descriptive protein-level context across tumor grades. Results: Transcriptomic comparisons of tumor samples with benign controls identified a set of shared transcriptional changes present in both low- and high-grade disease. Among these, SLC29A2 and IL2RA showed consistent upregulation across tumor grades and similar expression trends in external datasets. Direct comparison between HG and LG tumors revealed distinct transcriptional profiles with patterns indicative of increased proliferative activity and altered immune-related signaling in higher-grade disease. Pathway-level analyses showed the enrichment of cell-cycle and metabolic gene signatures in HG tumors, whereas inflammatory and NF-κB-associated transcriptional signatures showed a comparatively reduced expression. Additional genes, including AAMDC, ASAH2, TNFRSF1B, NFKBIL1, and NFKBIZ, were associated with these grade-dependent differences. qRT-PCR findings were generally consistent with the RNA-seq results for selected targets. Conclusions: This study describes transcriptional patterns associated with the PC grade in a MENA cohort using a pathology-guided framework. The findings highlight candidate genes associated with tumor presence and grade progression and provide a foundation for further investigation in larger, well-annotated cohorts, particularly in populations that remain underrepresented in transcriptomic studies. Full article

Background: The Warburg effect is a metabolic phenomenon observed in cancer cells that is characterized by aerobic glycolysis instead of mitochondrial oxidative phosphorylation as the primary mechanism of cellular energy generation. The exact benefit of such a metabolic switch is poorly understood, as aerobic glycolysis is thermodynamically more inefficient than mitochondrial oxidative phosphorylation. Case Presentation: Here, we present a case of a middle-aged individual with advanced stage 4 hepatocellular carcinoma with chronically low glucose levels measured in the 20 s to 40 s and completely asymptomatic. Upon examination, findings of sympathetic hyperactivity in the setting of hypoglycemia were absent, and mentation was completely intact. This occurred in the absence of any states or medications known to induce hypoglycemia; concurrently, the patient demonstrated hyperphagia, suggesting increased metabolic demand in the setting of an immense, overwhelming tumor burden. During these hypoglycemic intervals, the patient’s coagulation profile, including PT and international normalized ratio, remained within normal limits, suggesting sufficient residual hepatic parenchyma and glucogenic capacity. The patient’s glucose remained extremely low, refractory to correction with multiple dextrose, D5, and D10 administrations. This suggests chronic systemic habituation to malignant cell consumption of serum glucose leading to adaptations to this hypoglycemia in highly metabolically active organs, such as the brain, heart, liver, and kidneys. Discussion and Conclusions: This report highlights the clinical utility of recognizing this metabolic state in the setting of advanced-stage malignancy with significant tumor burden and how it affects hospital glucose management. Its early recognition will lead to improvements in meeting the patient’s metabolic demands while avoiding paradoxical exacerbation of lactic acidosis when providing guideline-directed oncological treatment. This metabolic state holds the potential to function as a surrogate marker, in conjunction with serum markers and imaging studies, for clinical identification of otherwise clinically silent advanced stage malignancies and for treatment escalation. Full article

Triple-negative breast cancer (TNBC) is an aggressive and clinically heterogeneous breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression, limited targeted treatment options, early relapse, and frequent development of therapy resistance. Although TNBC often shows initial sensitivity to chemotherapy, durable responses are commonly undermined by the emergence of adaptive resistant cell states rather than solely by fixed genetic mutations. This review synthesizes the role of epigenetic plasticity as a central mechanism that enables TNBC cells to dynamically reprogram transcriptional identity, survive therapeutic stress, and transition between epithelial, mesenchymal, stem-like, immune-evasive, and drug-tolerant persister phenotypes. Key epigenetic mechanisms include aberrant DNA methylation, histone acetylation and methylation, BET/BRD4-dependent transcriptional regulation, EZH2-mediated repression, SWI/SNF-dependent chromatin remodeling, non-coding RNA networks, and three-dimensional genome reorganization. These processes regulate tumor suppressor silencing, DNA-damage repair, epithelial–mesenchymal plasticity, cancer stem-cell maintenance, metabolic adaptation, immune-checkpoint regulation, and minimal residual disease. The review also highlights the translational relevance of epigenetic biomarkers, including DNA methylation signatures, circulating epigenetic markers, chromatin-accessibility profiles, and single-cell epigenomic approaches for diagnosis, prognosis, therapy prediction, and monitoring resistance evolution. Finally, therapeutic strategies targeting epigenetic plasticity are discussed, including DNMT, HDAC, BET, EZH2, KDM, and LSD1 inhibitors, with emphasis on rational combination approaches involving chemotherapy, PARP inhibitors, immunotherapy, and metabolic targeting. Overall, epigenetic plasticity represents both a major driver of TNBC resistance and a therapeutically exploitable vulnerability, provided those future strategies account for tumor heterogeneity, adaptive cell-state transitions, biomarker-guided patient selection, and combination-based treatment design. Full article

The aryl hydrocarbon receptor (AHR) and the vitamin D receptor (VDR) were long regarded as independent transcription factors governing distinct physiology—xenobiotic sensing and calcium–vitamin D homeostasis, respectively. AHR, a basic helix–loop–helix/PAS protein, heterodimerizes with ARNT and binds xenobiotic response elements (XREs) to drive cytochrome P450 genes such as CYP1A1; VDR, a nuclear receptor activated by 1,25-dihydroxyvitamin D₃, heterodimerizes with RXR and binds vitamin D response elements (VDREs). Although their genes reside on separate chromosomes (AHR, Chr 7; VDR, Chr 12), an integrated view recognizes the two pathways as extensively cross-regulatory. This review synthesizes the molecular, immunological, and tissue-level evidence for VDR–AHR interplay. At the molecular level, the receptors cooperate at composite promoter architectures—most notably an everted-repeat VDRE positioned adjacent to an XRE in the CYP1A1 promoter—while AHR ligands reciprocally enhance CYP24A1-mediated catabolism of active vitamin D. Tryptophan metabolism provides a bidirectional hub: kynurenine and the UVB photoproduct FICZ serve as endogenous AHR ligands whose balance, modulated by VDR, shapes signaling output. The tumor suppressor p53 functions as a shared upstream regulator coupling genotoxic stress to both receptors, with convergence on the CDKN1A (p21) checkpoint. Functionally, AHR and VDR converge on the regulatory T cell (Treg)/Th17 axis to influence immune tolerance: sustained AHR activation by TCDD favors Foxp3⁺ Treg differentiation, transient FICZ-driven activation promotes Th17 responses, and VDR reinforces the tolerogenic arm while independently repressing IL-17. The receptors further cooperate in maintaining intestinal epithelial barrier integrity and NF-κB restraint, with parallel impairment in inflammatory bowel disease, and are co-activated in skin by solar UVB, which simultaneously generates vitamin D₃ and the AHR ligand FICZ within keratinocytes. In cancer, VDR acts as a tumor suppressor, AHR exhibits context-dependent pro- and anti-tumor roles, and a three-way AHR–VDR–p53 interaction—inverted by mutant p53—forms a critical regulatory node. Throughout, the direction and magnitude of cross-talk prove highly dependent on cell type, ligand identity and kinetics, and species—distinctions often underappreciated in the literature. Clarifying these context-specific determinants is essential for translating AHR–VDR cross-regulation into rational therapies in autoimmunity, mucosal inflammation, dermatology, and oncology. Full article

Breast cancer remains one of the most common cancers in women, in which the majority of cases exhibit a hormone receptor-positive subtype. Although several treatment options are available for patients with this subtype, first-line therapies mainly rely on the patient’s sensitivity to endocrine therapy. Therapy resistance, which frequently develops over the treatment course, remains a key obstacle for clinical intervention. Efforts are currently underway to elucidate additional therapeutic targets to restore endocrine therapy sensitivity and treat hormone receptor-positive breast cancer. Here, we summarize work surrounding the sigma-2 receptor (σ2R) and its potential role in endocrine therapy resistance pathways, including PI3K-mTOR signaling and cholesterol metabolism. Although σ2R was pharmacologically characterized decades ago, its molecular identity remained elusive until 2017, when transmembrane protein 97 (TMEM97) was established as the sigma-2 receptor. TMEM97/σ2R is highly expressed in hormone receptor-positive breast cancer and its RNA expression levels are associated with endocrine resistance. High expression of TMEM97/σ2R elevates estrogen receptor activities and confers breast cancer cells with increased resistance to endocrine therapy via enhanced mTOR signaling. Given the role of TMEM97 in cholesterol homeostasis, understanding the connections between TMEM97/σ2R, breast cancer, and cholesterol regulation may reveal new pathways to aid in the development of targeted therapies. Evidence remains preclinical, and further investigation is needed to confirm hypothesized pathways involving TMEM97/σ2R in breast cancer endocrine resistance. Full article

Juvenile colorectal polyps (JP) are the most common polypoid lesions of the colon in children and the leading cause of lower gastrointestinal bleeding in pediatric patients. Although histologically classified as benign hamartomatous lesions, they arise in a context of allergic sensitization and IgE-mediated inflammation, suggesting that the epithelial compartment may play an active role in their pathogenesis. To date, most studies have focused on the immune cell infiltrate, leaving the molecular programs operating within the epithelium largely unexplored. Whole-transcriptome RNA sequencing (RNA-seq) was performed on epithelial cells isolated from pediatric JP (n = 8) and paired tissue circumjacent to polyp (TCP) (n = 7) obtained from children with a history of rectal bleeding and IgE sensitization to food allergens. Differential expression, functional enrichment (GO, KEGG, GSEA), and cross-dataset comparison with TCGA colorectal adenocarcinoma (CRC) was conducted. Candidate genes were validated by RT-qPCR in independent samples, including colorectal cancer (CRC) and inflammatory bowel disease (IBD) tissue. Differential expression analysis identified 3273 differentially expressed genes (2342 upregulated, 931 downregulated in JP vs. TCP), with 220 genes exceeding 32-fold change, including SERPINB3 (log2FC = 12.16), MMP1 (log2FC = 10.19), NMUR2 (log2FC = 10.08) and CHI3L1 (log2FC = 8.87). JP epithelium displayed a coherent type 2 inflammatory signature, encompassing upregulation of the alarmin IL33, eosinophil-attracting chemokines (CCL11, CCL24), IgE receptor subunits (FCER1A, FCER1G), and a coordinately activated leukotriene and prostaglandin biosynthetic program (ALOX5, ALOX5AP, PTGS2). Concurrent alterations in epithelial identity were observed, including downregulation of absorptive enterocyte and intestinal stem cell markers (CDX2, LGR5, ASCL2) alongside upregulation of secretory and regenerative programs, including the ectopic gastric-type mucin MUC5AC. Tight junction dysregulation—notably upregulation of the pore-forming claudin CLDN2 and loss of barrier-sealing claudins (CLDN3, CLDN4, CLDN23)—was consistent with impaired epithelial permeability. Pathway analyses confirmed activation of type 2 immune and extracellular matrix remodeling programs, with concurrent suppression of mitochondrial oxidative phosphorylation. Cross-dataset comparison with TCGA CRC data identified 381 co-upregulated and 87 co-downregulated genes shared between JP and CRC, including SERPINE1, CXCL8, ICAM1, and MMP3, several of which were associated with poorer disease-specific survival in CRC patients. RT-qPCR validation confirmed elevation of CHI3L1 and SERPINE1 in both JP and CRC, while SERPINB4 appeared JP-specific. Epithelial cells from pediatric juvenile colorectal polyps associated with allergic sensitization display a comprehensive type 2 inflammatory transcriptome alongside profound alterations in lineage identity, barrier integrity, and metabolic programming. Partial convergence with CRC-associated gene expression programs—in the absence of histological dysplasia—suggests that chronic allergic inflammation activates conserved epithelial remodeling pathways shared across mucosal tissues. CHI3L1, SERPINE1, and SERPINB4 are candidate biomarkers warranting validation in larger cohorts. Full article

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle loss, affecting 30–60% of patients with advanced renal cell carcinoma (RCC). It significantly impacts treatment tolerance, quality of life, and prognosis, yet its diagnosis and management remain challenging due to fragmented RCC-specific evidence, particularly in the era of immune checkpoint inhibitor (ICI)-based therapy. The pathogenesis involves persistent systemic inflammation, metabolic reprogramming, and tumor–host interactions. The IL-6/STAT3 and TNF-α/NF-κB pathways are central to muscle catabolism, while tumor-derived mediators such as GDF15 and PTHrP, along with mitochondrial dysfunction, further drive cachexia progression. For prognostic assessment, CT-derived skeletal muscle mass evaluation combined with systemic inflammatory and nutritional biomarkers—including neutrophil-to-lymphocyte ratio (NLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), and cachexia index (CXI)—has improved risk stratification in advanced RCC. Preclinical and emerging clinical data suggest that targeted therapies may partially attenuate cachexia by modulating inflammatory signaling, while multimodal interventions integrating nutritional support and exercise rehabilitation remain the cornerstone of management. Novel strategies, such as inhibition of the GDF15/GFRAL axis, are under active investigation. Future research should prioritize identification of early biomarkers, standardization of cachexia assessment, and prospective evaluation of cachexia-directed interventions in the immunotherapy era. Integrating cachexia assessment into routine practice may ultimately enable personalized treatment and improve long-term outcomes for patients with advanced RCC. Full article

Colorectal cancer (CRC) has shown significant heterogeneity regarding its response to immunotherapy. Long-lasting, beneficial effects have been observed in mismatch repair-deficient, microsatellite instability-high (dMMR/MSI-H) tumours, while mismatch repair-proficient, microsatellite stable (pMMR/MSS) tumours have remained resistant. Such differences in results have been studied in this review through the “hot” and “cold” tumour concept. It explains how various biological and microenvironmental factors play a role in immune resistance and T-cell priming and infiltration. Key factors include a low neoantigen load and defects in antigen presentation, which reduce the overall immune recognition of tumour cells. The review also studies certain processes such as Wnt/β-catenin and mitogen-activated protein kinase (MAPK) signalling and what input they have in the prevention of effective antitumour immune responses. Conventional treatments like chemotherapy and radiotherapy have been considered alongside more targeted treatments such as the inhibition of vascular endothelial growth factor (VEGF) signalling and the suppression of myeloid-mediated immune evasion, to convert “cold” MSS tumours into immune-responsive lesions. Methods which aim to modify the tumour microenvironment such as metabolic reprogramming and microbiome modulation have also been covered in this review. Artificial intelligence and nanomedicine are new technologies that could provide improved patient stratification and therapeutic precision, although their clinical application in pMMR/MSS CRC remains under investigation. A systematic literature search of PubMed and PubMed Central (PMC) was conducted from 10 June 2026 to 19 August 2026 using predefined eligibility criteria, with study selection reported according to PRISMA 2020. Because of substantial heterogeneity in study design, therapeutic approach and reported outcomes, the included evidence was synthesized narratively rather than by meta-analysis. A total of 158 studies were included. Full article