In this review, the historical development of tumor response criteria is examined and an interview was conducted with one of the original researchers behind the original study. This study, published nearly five decades ago, assessed tumor size through palpation and measurements of simulated tumor masses ("balls under mattresses"). The methodology used in that early study as well as in subsequent research that has influenced modifications of the current response evaluation criteria was critically evaluated.

Fibrolipomatous hamartomas (FLHs) are rare pathologies almost exclusively involving the median nerve. Rarer is extra-median involvement of FLH, especially in nerves outside of the upper extremity. In this case report, we detail the case of a 48-year-old male with FLH involving his right tibial nerve-the first in reported literature in this nerve distribution to our knowledge- and perform a review of the existing case reports on extra-median FLH within the English-based literature.

Intrahepatic biliary neuroendocrine neoplasms (NENs) are rare neoplasms originating from neuroendocrine cells in the intrahepatic bile ducts. Patients often present without hormone-related symptoms but are admitted due to jaundice or abdominal pain.

Drug repurposing offers a cost-effective and time-efficient strategy for identifying new cancer therapies. Sertraline, a widely prescribed selective serotonin reuptake inhibitor (SSRI), has shown promising anticancer properties through modulation of key pathways involved in tumor survival, stress adaptation, and therapeutic resistance. This scoping review systematically evaluates the current evidence on sertraline's anticancer mechanisms, efficacy, and translational potential. A systematic search of PubMed, EMBASE, Scopus, and Web of Science was conducted in accordance with PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, mechanisms, assays, and outcomes were extracted and synthesized. Of 97 screened articles, 67 met inclusion criteria, comprising 56 preclinical studies, nine population-based studies, and two mixed-methods reports. Sertraline induces apoptosis via mitochondrial dysfunction, caspase activation, and Bcl-2 downregulation, disrupts autophagy and the unfolded protein response, and impairs serine/glycine metabolism through SHMT inhibition. It also suppresses oncogenic signaling via mTOR and TCTP modulation. In vivo studies confirmed tumor growth inhibition in various cancer models, including breast, lung, glioblastoma, and liver. Sertraline enhances the efficacy of chemotherapy, radiotherapy, and targeted therapies by sensitizing resistant cells, modulating immune responses, and impairing metabolic recovery. Retrospective studies suggest no increased cancer risk with SSRI use and hint at protective associations in select malignancies. While current evidence is predominantly preclinical, sertraline's multi-targeted action and established safety profile support its candidacy for repurposing. Further translational research and biomarker-driven clinical trials are warranted to validate its therapeutic niche and optimize its integration into oncology.

Colon cancer persists as a major global health burden due to therapy resistance and metastasis, with tumor-associated macrophages (TAMs) in the microenvironment driving progression through immune evasion and angiogenesis. This review highlights plant-derived therapeutics targeting TAMs to disrupt protumor signaling. Key phytochemicals (e.g., Curcumin, Cucurbitacin B, Astragaloside IV) suppress M2 polarization via NF-κB/STAT3 inhibition, block VEGF/HIF-1α-mediated angiogenesis, and enhance antitumor immunity by downregulating PD-L1. Cannabidiol, Hydroxygenkwanin regulate TAM metabolism. Dietary agents like sulforaphane and β-glucans modulate TAM-gut microbiome crosstalk. Nanoparticle-encapsulated phytochemicals enhance TAM-targeted delivery, while clinical translation requires standardized phytopreparations and biomarker-guided trials. We propose integrating validated botanical adjuvants (e.g., Fucoidan for TLR4 inhibition, dihydroisotanshinone I for CCL2 suppression) with immunotherapies to remodel immunosuppressive niches. Phytotherapy offers a multifaceted strategy to overcome TAM-driven therapeutic barriers in colon cancer, emphasizing plant-based precision medicine to augment conventional treatments.

Ovarian cancer (OC) remains one of the leading causes of gynecologic cancer-related mortality, with most patients presenting with disseminated disease, particularly within the peritoneal cavity. Standard treatment includes cytoreductive surgery, platinum-based chemotherapy, and targeted maintenance approaches depending on the patient's and tumor's genetic profile. Despite treatment advancements, approximately 25% of high-grade serous OC cases relapse within a year despite optimal primary treatment with complete tumor clearance at cytoreduction. Advances in contrast-enhanced CT (CE-CT) and MRI have revolutionized the evaluation and treatment planning of advanced OC. CT remains the gold standard for staging and assessing tumor extent, effectively identifying peritoneal, lymphatic, and distant metastases. However, it is less effective in detecting small-volume peritoneal dissemination. MRI, with superior soft-tissue contrast, complements CT by providing a detailed assessment of peritoneal disease, characterizing sonographically indeterminate adnexal masses. Diffusion-weighted imaging and gadolinium-enhanced MRI have improved the diagnostic sensitivity for peritoneal disease but are unable to predict treatment response, recurrence risk, and prognosis. Radiomics, which extracts quantitative tumor features from imaging data, holds promise for personalizing treatment and identifying patients at risk for early recurrence despite optimal therapy. The integration of CT, MRI, and radiomics could enhance surgical planning and improve long-term survival outcomes in patients with advanced OC.

Mycosis is caused by, among other factors, filamentous fungi, ubiquitous molds belonging to Aspergillus spp. which are often opportunistic pathogens. Over 100 species of Aspergillus have been described. The most common species responsible for diseases in humans and animals are Aspergillus fumigatus and Aspergillus niger, with Aspergillus flavus and Aspergillus clavatus being somewhat rarer. Aspergillus causes a range of diseases, from localized colonization and hypersensitivity reactions, through chronic necrotizing infections, to rapidly progressing angioinvasion and dissemination, leading to death. Testicular mycosis is extremely rarely described in both humans and animals. No studies in the literature report a simultaneous occurrence of testicular tumors and fungal infection of the organ, so the aim of this paper was to describe, for the first time, a case of two independent testicular tumors coexisting with testicular mycosis. A histopathological examination was performed on the left testicle of a male dog, specifically a mixed-breed dog resembling a husky weighing 22 kg and with an age of 8 years. Bilateral orchidectomy was performed for medical reasons due to the altered outline of the left testicle, leading to scrotal deformation. The dog did not show any clinical signs of illness, and the testicles were not painful. The right testicle, according to the operating veterinarian, showed no macroscopic changes, so histopathological verification was not performed. Microscopic imaging of the changes clearly indicated the coexistence of a tumor process involving Leydig cells (Leydigoma, interstitial cell tumor, ICT), Sertoli cells (Sertolioma), and fungal infection of the testis. The case suggests the possibility of the coexistence of tumor processes, which may have impaired local immune response of the tissue, with an infectious, in this case fungal, inflammatory process. Based on the literature, this paper is the first report on the occurrence of two independent histotype testicular tumors and their associated mycosis.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by a clinical and/or biochemical hyperandrogenism. In addition, PCOS is also associated with the presence of ovarian cysts, anovulation, and menstrual abnormalities such as oligomenorrhea or amenorrhea. The aetiology of the syndrome is multifactorial and heterogeneous due to the interaction of genetic, hormonal, metabolic, and environmental factors, as well as the different phenotypes and responses to treatments exhibited by the patients. Considering this complex interaction, it is essential to continue with the research focused on the mechanisms involved in the development and maintenance of the pathology. The alteration in the pulsatile secretion of the gonadotropin-releasing hormone (GnRH) is considered to be one of the main causes that contributes to its onset. In this review, we discuss recent evidence about the role of the rostral periventricular area of the third ventricle (RP3V), the arcuate nucleus (ARC), and the ventromedial nucleus of the hypothalamus (VMH), key hypothalamic regions that regulate GnRH secretion, in the development of PCOS. In addition, we analyse the clinical, metabolic, and endocrine factors that interact in the patients with PCOS, offering a multifactorial perspective to improve our understanding of this disorder.

The 2021 WHO classification of brain tumours revolutionised the oncological field by emphasising the role of molecular, genetic and pathogenetic advances in classifying brain tumours. In this context, incidental gliomas have been increasingly identified due to the widespread performance of standard and advanced MRI sequences and represent a diagnostic and therapeutic challenge. The impactful decision to perform a surgical procedure deeply relies on the non-invasive identification of features or parameters that may correlate with brain tumour genetic profile and grading. Therefore, it is paramount to reach an early and proper diagnosis through neuroradiological techniques, such as MRI. Standard MRI sequences are the cornerstone of diagnosis, while consolidated and emerging roles have been awarded to advanced sequences such as Diffusion-Weighted Imaging/Apparent Diffusion Coefficient (DWI/ADC), Perfusion-Weighted Imaging (PWI), Magnetic Resonance Spectroscopy (MRS), Diffusion Tensor Imaging (DTI) and functional MRI (fMRI). The current novelty relies on the application of AI in brain neuro-oncology, mainly based on radiomics and radiogenomics models, which enhance standard and advanced MRI sequences in predicting glioma genetic status by identifying the mutation of multiple key biomarkers deeply impacting patients' diagnosis, prognosis and treatment, such as IDH, EGFR, TERT, MGMT promoter, p53, H3-K27M, ATRX, Ki67 and 1p19. AI-driven models demonstrated high accuracy in glioma detection, grading, prognostication, and pre-surgical planning and appear to be a promising frontier in the neuroradiological field. On the other hand, standardisation challenges in image acquisition, segmentation and feature extraction variability, data scarcity and single-omics analysis, model reproducibility and generalizability, the black box nature and interpretability concerns, as well as ethical and privacy challenges remain key issues to address. Future directions, rooted in enhanced standardisation and multi-institutional validation, advancements in multi-omics integration, and explainable AI and federated learning, may effectively overcome these challenges and promote efficient AI-based models in glioma management. The aims of our multidisciplinary review are to: (1) extensively present the role of standard and advanced MRI sequences in the differential diagnosis of iLGGs as compared to HGGs (High-Grade Gliomas); (2) give an overview of the current and main applications of AI tools in the differential diagnosis of iLGGs as compared to HGGs (High-Grade Gliomas); (3) show the role of MRI, radiomics and radiogenomics in unravelling glioma genetic profiles. Standard and advanced MRI, radiomics and radiogenomics are key to unveiling the grading and genetic profile of gliomas and supporting the pre-operative planning, with significant impact on patients' differential diagnosis, prognosis prediction and treatment strategies. Today, neuroradiologists are called to efficiently use AI tools for the in vivo, non-invasive, and comprehensive assessment of gliomas in the path towards patients' personalised medicine.

Background: Circulating tumor DNA (ctDNA), shed into bodily fluids by cancer cells through apoptosis, necrosis, or active secretion, is currently used in the field of genomic investigation in clinical settings, primarily for advanced stages of non-small-cell lung cancer (NSCLC). However, its potential role in guiding the multi-omic approach to early-stage NSCLC is emerging as a promising area of investigation. Efforts are being made to integrate the genomics not only in surgery, but also in the definition of long-term prognosis after surgical or radiotherapy and for the prediction of recurrence. Methods: An extensive literature search was conducted on PubMed, covering publications from 2000 to 2024. Using the advanced search tool, titles and abstracts were filtered based on the following keywords: ctDNA, early stage, NSCLC. From this search, 20 studies that fulfilled all inclusion criteria were selected for analysis in this review. Results: This review highlights the growing body of evidence supporting the potential clinical use of ctDNA as a genomic biomarker in managing early-stage NSCLC. Baseline ctDNA levels offer valuable information about tumor molecular biology and histological characteristics. Beyond its prognostic value before treatment, liquid biopsy has proven useful for tracking minimal residual disease and forecasting recurrence following curative interventions such as surgery or radiotherapy. Future adjuvant treatment decisions may increasingly rely on predictive models that incorporate liquid biopsy findings alongside other clinical factors. Conclusions: The potential use of this analyte introduces new opportunities for the integration of genomic data in treatment, as well as relapse monitoring with more accurate and innovative than traditional methods, particularly in patients with early-stage NSCLC.

Lung cancer (LC), with non-small-cell lung cancer (NSCLC) as its predominant subtype, remains the leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors (ICIs) have redefined the therapeutic paradigm in advanced NSCLC, durable responses are confined to a limited subset of patients. A major clinical challenge persists: the inability to accurately predict which patients will derive meaningful benefit, which will exhibit primary resistance, and which are at risk for severe immune-related toxicities. The imperative to individualize ICI therapy necessitates robust, dynamic, and accessible biomarkers. Liquid biopsy has emerged as a transformative, minimally invasive tool that enables real-time molecular and immunologic profiling. Through analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and peripheral blood immune components, liquid biopsy offers a window into both tumor intrinsic and host-related determinants of ICI response. These biomarkers not only hold promise for identifying predictive signatures-such as tumor mutational burden, neoantigen landscape, or immune activation states-but also for uncovering mechanisms of acquired resistance and guiding treatment adaptation. Beyond immunotherapy, liquid biopsy plays an increasingly central role in the landscape of targeted therapies, allowing early detection of actionable driver mutations and resistance mechanisms (e.g., EGFR T790M, MET amplification, and ALK fusion variants). Importantly, serial sampling via liquid biopsy facilitates longitudinal disease monitoring and timely therapeutic intervention without the need for repeated tissue biopsies. By guiding therapy selection, monitoring response, and detecting resistance early, liquid biopsy has the potential to significantly improve outcomes in NSCLC.

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut-liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host-microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut-liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA.

About 10% of all forms of melanoma occur in a familial context and may be due to germline predisposing mutations transmitted as autosomal dominant traits within the affected families. CDKN2A is a highly penetrant gene associated to familial melanomas, being responsible of up to 40% of the cases. Other high, moderate, and low penetrance genes are being discovered, even if their own contribution to melanoma risk is still under debate. Indeed, next generation sequencing-based strategies enable large genomic regions to be analyzed, thus identifying novel candidate genes. These strategies, in diagnostic settings, may also improve the identification of the hereditary cases between all melanomas. The identification of the at-risk subjects gives an important opportunity for cancer surveillance in order to reduce the risk of onset and/or make early diagnosis. In addition, the identification of molecular biomarkers may drive the future development of specific targeted therapies, as already done for other inherited cancer syndromes. Here, we summarize the state of the art regarding the molecular basis of the hereditary susceptibility to develop melanoma.

Skin cancer is the most common cancer form worldwide, and it is primarily divided into melanoma and non-melanoma types, with non-melanoma being the most prevalent condition. Cutaneous squamous cell carcinoma (cSCC) accounts for 50% of primary skin cancers and is characterized by uncontrolled keratinocyte proliferation. cSCC's current standard treatment is surgical resection and chemotherapy. Unfortunately, these methods often lead to disfigurement, functional morbiditly, and compromised function. In contrast to immunotherapy, emerging scenarios have shown promising results, especially in neoadjuvant settings. Cemiplimab (Libtayo®; Regeneron, Tarrytown, NY, USA), a PD-1 monoclonal antibody, has shown efficacy in treating advanced or metastatic cSCC, and its use as a neoadjuvant therapy has been recently explored. This review aims to evaluate Cemiplimab in the neoadjuvant setting for cSCC treatment. The Methodology followed PRISMA guidelines, this review analyzed studies on Cemiplimab as a neoadjuvant therapy for cSCC that were sourced from PubMed, Web of Science, and Scopus. Only controlled trials, cohort studies, case series, and systematic reviews were included. From 341 records, 21 studies were included, and six clinical trials provided key data about neoadjuvant Cemiplimab's response rates, efficacy, adverse effects, and safety considerations. The targeted data revealed a neoadjuvant Cemiplimab mean pathologic response rate of 72%, with a 62% objective response rate. Treatment-related adverse events (TRAEs) affect 66% of patients, though most cases are not severe. The most common include fatigue, maculopapular rash, and diarrhea. The studies showed high rates of complete pathological responses (cPRs) and major pathological responses (mPRs), suggesting a strong therapeutic potential. Neoadjuvant Cemiplimab for cSCC therapy shows high response rates, low recurrence, improved survival, and manageable side effects. The current literature indicates that Cemiplimab may also be effective when used in immunosuppressed patients. Despite more research still being needed to confirm its long-term benefits and the effects of the drug's use outside of clinical trials, there is strong evidence to consider neoadjuvant Cemiplimab as a promising and efficient treatment.

UDP-Gal-β-1,4 galactosyltransferase-V (GalT-V) is a member of a large family of galactosyltransferases whose function is to transfer galactose from the nucleotide sugar UDP-galactose to a glycosphingolipid glucosylceramide, to generate lactosylceramide (LacCer). It also causes the N and O glycosylation of proteins in the Trans Golgi area. LacCer is a bioactive lipid second messenger that activates an "oxidative stress pathway", leading to critical phenotypes, e.g., cell proliferation, migration angiogenesis, autophagy, and apoptosis. It also activates an "inflammatory pathway" that contributes to the progression of disease pathology. β-1,4-GalT-V gene expression is regulated by the binding of the transcription factor Sp-1, one of the most O-GlcNAcylated nuclear factors. This review elaborates the role of the Sp-1/GalT-V axis in disease phenotypes and therapeutic approaches targeting not only Sp-1 but also Notch-1, Wnt-1 frizzled, hedgehog, and β-catenin. Recent evidence suggests that β-1,4GalT-V may glycosylate Notch-1 and, thus, regulate a VEGF-independent angiogenic pathway, promoting glioma-like stem cell differentiation into endothelial cells, thus contributing to angiogenesis. These findings have significant implications for cancer and cardiovascular disease, as tumor vascularization often resumes aggressively following anti-VEGF therapy. Moreover, LacCer can induce angiogenesis independent of VEGF and its level are reported to be high in tumor tissues. Thus, targeting both VEGF-dependent and VEGF-independent pathways may offer novel therapeutic strategies. This review also presents an up-to-date therapeutic approach targeting the β-1,4-GalT-V interactome. In summary, the β-1,4-GalT-V interactome orchestrates a broad network of signaling pathways essential for maintaining cellular homeostasis. Conversely, its dysregulation can promote unchecked proliferation, angiogenesis, and inflammation, contributing to the initiation and progression of multiple diseases. Environmental factors and smoking can influence β-1,4-GalT-V expression and its interactome, whereas elevated β-1,4-GalT-V expression may serve as a diagnostic biomarker of colorectal cancer, inflammation-exacerbated by factors that may worsen pre-existing cancer malignancies, such as smoking and a Western diet-and atherosclerosis, amplifying disease progression. Increased β-1,4-GalT-V expression is frequently associated with tumor aggressiveness and chronic inflammation, underscoring its potential as both a biomarker and therapeutic target in colorectal and other β-1,4-GalT-V-driven cancers, as well as in cardiovascular and inflammatory diseases.

Therapeutic resistance remains a critical barrier in effective cancer treatment, contributing to disease recurrence, progression, and reduced patient survival. In recent years, natural bioactive compounds have emerged as promising adjuncts in oncology due to their ability to modulate multiple biological processes involved in resistance. This review explores current evidence on the role of natural compounds in influencing cancer cell behavior and their interactions with the tumor microenvironment. By organizing these compounds into chemical families, we provide a structured overview of their potential to enhance the efficacy of standard chemotherapy and reduce resistance-related mechanisms. We also highlight innovative strategies, including combination therapies and advanced drug delivery systems, that aim to improve their clinical applicability. Overall, this work underscores the relevance of integrating natural bioactives into modern cancer therapy and calls for further translational research to bridge preclinical findings with clinical implementation.

Artificial intelligence (AI) and its machine learning and deep learning algorithms have shown promise in oncological practice. Spatial information analysis in the context of cancer is crucial for its diagnosis and treatment because it can provide an understanding of tumor-microenvironment interactions and reveal insights into response to treatment. AI tools can analyze spatial information at multiple scales, highlighting key disease, clinical, and genetic phenotypes that may reveal underlying mechanisms and molecular markers of response and resistance within the tumor and its microenvironment. By examining tumor interactions at macroscopic (diagnostic imaging) and microscopic (pathology slides and spatial biology) levels, AI can assist in making important diagnostic and prognostic decisions. In this review, we first present an overview of AI and the need for multiscale spatial information in oncology. Then, we examine growing AI applications in the analysis of such information, focusing on diagnostic imaging, digital pathology, and spatial molecular biology. We also discuss applications of large-scale foundation models and task-oriented agentic AI in these fields as emergent technologies. Then, we discuss current limitations for the clinical translation of AI into regular utilization in cancer care and discovery.

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with a growing incidence and significant molecular heterogeneity that challenges traditional diagnostic and management paradigms. While histopathological assessment remains the gold standard for diagnosis, emerging liquid biopsy technologies provide promising non-invasive alternatives for tumor detection, molecular profiling, and disease monitoring. This review comprehensively explores the current landscape and clinical utility of liquid biopsy analytes-including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), extracellular RNAs, and exosomes-in the context of EC. We discuss the evolving role of pathologists in integrating molecular data with histomorphological features to enhance diagnostic precision, prognostic stratification, and therapeutic decision-making. Novel technologies such as methylation-based assays, tumor-informed ctDNA sequencing, and tumor-educated platelets (TEPs) are highlighted for their diagnostic accuracy and potential for early detection. Furthermore, we summarize key clinical trials and future directions aimed at validating liquid biopsy platforms for routine clinical implementation. As EC care transitions toward a precision oncology model, the integration of liquid biopsy with traditional surgical pathology offers a transformative approach to individualized and personalized patient management.

Glioblastoma (GBM) is a highly aggressive brain tumour characterised by a poor prognosis and resistance to anti-angiogenic treatments. Vasculogenic mimicry (VM), in which tumour cells form vessel-like structures independent of endothelial cells, has emerged as a key mechanism hindering the efficacy of anti-angiogenic therapies. Recent research highlights the central role of RNA-binding proteins (RBPs) in regulating VM through diverse post-transcriptional mechanisms, including mRNA decay induction and translational repression. Several oncogenic RBPs, such as HuR and HNRNPs, promote VM and tumour aggressiveness, while others, including RBMS3, act as suppressors of VM. Despite the prominent oncogenic roles of multiple RBPs, RBP-targeting compounds aimed at suppressing VM in GBM have remained at an early stage due to a number of limitations. This review summarises the role of VM in the treatment resistance of GBM, RBP regulation of VM, and the current landscape and future direction of RBP-targeted therapies aimed at overcoming VM-mediated treatment resistance in GBM.

Breast cancer is one of the most common cancers globally. Unfortunately, many patients with breast cancer develop resistance to chemotherapy and tumor recurrence, which is primarily driven by breast cancer stem cells (BCSCs). BCSCs behave like stem cells and can self-renew and differentiate into mature tumor cells, enabling the cancer to regrow and metastasize. Key markers like CD44 and aldehyde dehydrogenase-1 (ALDH1), along with pathways like Wingless-related integration site (Wnt), Notch, and Hedgehog, are critical to regulating this stem-like behavior of BCSCs and, thus, are being investigated as targets for various new therapies. This review summarizes marker-dependent strategies for targeting BCSCs and expands on the challenges for the development of anti-BCSC drugs. We explore cutting-edge approaches like artificial intelligence (AI)-driven drug discovery and urge readers to seriously consider biological clocks and chronotherapy as experimental variables in drug discovery. Collectively, the task of cancer researchers is to overcome the many hurdles targeting BCSCs if we hope to tangibly improve breast cancer treatment outcomes and reduce mortality.