After about 20 years of exciting improvements in treatment efficacy outcomes of advanced epidermal growth factor receptor (EGFR) mutant and anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC), also combined with a progressively better safety profile, from chemotherapy to new generation tyrosine kinase inhibitors (TKIs) (osimertinib, alectinib, brigatinib), the recent MARIPOSA and CROWN trials have changed this trend. For the first time in the history of EGFR and ALK treatments, we must face the issue of being a step behind in terms of toxicity profile. The combination of amivantamab plus lazertinib in EGFR mutant NSCLC, and lorlatinib in ALK rearranged NSCLC, has improved efficacy outcomes as never before. The story would be easy and totally positive if these two innovative, amazing treatments were not associated with new peculiar features in safety profiles that must be discussed with patients, because they potentially affect their quality of life. When treating these patient populations, the peculiar safety profiles of amivantamab plu lazertinib and lorlatinib require a well-structured shared decision making, "where and when", both the high probability of a longer survival and the risk of worse quality of life must be well announced and explained to our patients before the shared final treatment choice.

Cholecystokinin A receptor (CCKAR) has been linked to poor prognosis in colon cancer patients, but the role of CCKAR in colon cancer cell invasiveness and the underlying mechanisms remain elusive. This study aimed to explore the effect of CCKAR on the invasive potential of colon cancer cells.

Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8+ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability-thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer-spanning glucose, amino acid, and lipid metabolism-and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.

Disulfidptosis is a newly identified form of regulated cell death (RCD) first described in 2023, representing a significant advance in understanding programmed cell death pathways. This unique cell death modality is characterized by abnormal intracellular accumulation of disulfide bonds and disruption of redox homeostasis, leading to cytoskeletal collapse without caspase activation. Disulfidptosis is primarily triggered by glucose deprivation in cells with high expression of solute carrier family 7 member 11 (SLC7A11). Under these conditions, insufficient NADPH supply prevents the effective reduction of accumulated cystine to cysteine, thereby inducing disulfide stress. Distinct from apoptosis, ferroptosis, cuproptosis, or pyroptosis, disulfidptosis exhibits unique metabolic dependencies and a hallmark feature of cytoskeletal disintegration. Current evidence indicates that this mechanism is operative in various tumor types, including hepatocellular carcinoma, colorectal cancer, and lung adenocarcinoma, suggesting its potential therapeutic relevance. Therapeutic strategies targeting disulfidptosis include modulation of metabolic pathways-such as the use of GLUT1 or G6PD inhibitors-to selectively induce this form of cell death in cancer cells. This review systematically summarizes current understanding, aiming to elucidate the unique mechanisms and therapeutic potential of disulfidptosis, and provides a foundational framework for future studies and the development of innovative strategies targeting tumor metabolic vulnerabilities.

Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with high recurrence rates. Lymphovascular invasion (LVI) predicts a poor prognosis, yet its molecular drivers remain unclear. BOC cell adhesion-associated, oncogene-regulated (BOC, also known as Brother of CDO [Cell adhesion molecule-Related/Down-regulated by Oncogenes]), a hedgehog-related cell surface receptor, may serve as a biomarker for tumor progression and chemotherapy response. The study aimed to investigate the role of BOC in UTUC and its potential to predict LVI and chemotherapy response.

Colorectal cancer (CRC) is the second deadliest cancer worldwide, being the presence of metastasis, mainly in the liver, a major contributor to high mortality rates in affected patients. The tumor microenvironment (TME)-comprised of interacting endothelial, stromal, and immune cells-plays a critical role in creating a supportive niche for tumor cell colonization and immune evasion and, thus, the establishment of metastases. The liver's intrinsic nature further facilitates the development of immune tolerance, mediated by regulatory T cells, myeloid-derived suppressor cells, and soluble factors such as anti-inflammatory cytokines, which together dampen antitumor immune responses. This immunosuppressive milieu contributes significantly to resistance to immune checkpoint inhibitors, limiting the efficacy of immunotherapy in metastatic CRC. Deciphering the complex crosstalk between metastatic CRC cells and TME within the liver is essential for developing novel, effective immunotherapeutic approaches. Several strategies to overcome this lack of response are under research, including combination therapies, novel compounds, and approaches that target TME components. The scope of this review is to synthesize recent advances in the characterization of the hepatic metastatic microenvironment and emerging therapeutic approaches aimed at overcoming immune resistance in CRC liver metastases.

The combination of atezolizumab plus bevacizumab (A+B) represents one of the standards first-line treatments for unresectable hepatocellular carcinoma (HCC). Metformin has garnered attention for its potential antitumour and immunomodulatory properties beyond glycaemic control. This study aimed to assess metformin's impact in patients with type 2 diabetes mellitus (T2DM) receiving A+B therapy.

Cutaneous squamous cell carcinoma (CSCC) is the second most common type of skin cancer and typically involves the head and neck. Systemic therapy is often required for patients with advanced CSCC to achieve optimal disease control. Immune checkpoint inhibitors (ICIs) are now the standard of care for these patients, with a 50%-60% response rate and sustainable remission for at least 30% of patients. Given the activity of ICIs in advanced head and neck CSCC, ICIs are being studied in early-stage disease or neoadjuvant situations. The purpose of this review is to provide an overview of the innovative perioperative strategies in resectable disease and discuss novel immunotherapeutic strategies designed to overcome treatment resistance. In conclusion, neoadjuvant ICIs have demonstrated impressive response rates with unclear survival benefit. The effectiveness of adjuvant ICIs is currently being explored. Emerging biomarkers, such as circulating tumor DNA (ctDNA), will be crucial for optimizing patient selection and improving treatment outcomes.

Androgen receptor (AR) signaling is a central driver of prostate cancer progression, yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized. This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer (HSPC) through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.

Piwi-associated RNAs are small non-coding RNAs implicated in cancer, yet few have been characterized in colorectal cancer (CRC). This study aimed to identify a CRC-related piRNA and investigate its clinical relevance, biological function, and biomarker potential.

Lactate, as a critical byproduct of tumor metabolic reprogramming, plays an important role in DNA damage repair and tumor immune infiltration. This work aims to elucidate the molecular mechanisms by which lactate promotes tumor DNA damage repair (DDR) and subsequent immune evasion.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by a highly immunosuppressive tumor microenvironment (TME), dense stromal architecture, and limited response to conventional therapies. This review comprehensively examines the emerging role of chimeric antigen receptor (CAR)-engineered immune cells, including chimeric antigen receptor-T (CAR-T), CAR-macrophages (CAR-M), and CAR-natural killer (CAR-NK) cells, as innovative immunotherapeutic strategies for PDAC. We delve into the mechanistic foundations of these platforms, highlighting their unique abilities to target tumor-associated antigens, overcome stromal barriers, and remodel the immunosuppressive TME. Recent preclinical and clinical advances demonstrate promising antitumor activity, particularly with targets such as mesothelin, claudin18.2, and human epidermal growth factor 2 (HER2), though challenges related to antigen heterogeneity, TME suppression, and cell persistence remain. We further discuss synergistic approaches involving genetic engineering, microenvironment modulation, and combination therapies aimed at enhancing efficacy. Finally, we offer perspectives on the future direction of CAR-based therapies, including the development of next-generation constructs, allogeneic "off-the-shelf" products, and personalized combination regimens, underscoring their potential in pancreatic cancer.

Prostate cancer cells often develop mechanisms to evade conventional therapies. Nanomedicine offers the potential for targeted drug delivery, improved tumor accumulation, and reduced systemic toxicity. This study biosynthesizes silver nanoparticles (NPP/AgONPs) functionalized with propolis, evaluates their antibacterial efficacy against uropathogenic strains of Escherichia coli (E. coli), and assesses their cytotoxic effect on cancer cell proliferation using the PC-3, human prostate epithelial cell line.

Cancer-associated fibroblasts (CAFs) play critical roles in tumor progression and immunosuppression; however, their contribution to the functional classification and personalized treatment of gastric cancer remains poorly defined. This study aimed to identify effective therapeutic targets to facilitate individualized treatment strategies for patients with gastric cancer.

Prostate cancer is the second most common fatal cancer in men. Identifying new biological therapeutic targets is crucial to effectively improve the prognosis of prostate cancer patients. Ovarian tumor family deubiquitinase 4 (OTUD4) is a member of the ovarian tumor-associated protease domain (OTUDs) family. Although previous studies have shown that the expression and function of OTUD4 vary across different tumors, its role in prostate cancer remains unknown. The aim of this study is to explore new therapeutic targets and diagnostic markers for prostate cancer and investigate their mechanisms of action.

An increasing number of studies have shown that ferroptosis is related to the initiation and development of small cell lung cancer (SCLC). The systematic review aimed to summarize the characteristics of ferroptosis from its pathogenetic role to translational therapeutic implications in SCLC.

A 15-month-old intact female rat was presented with worsening lethargy and dysorexia present for 1 wk and bruxism present for 3 d. The diet was fruits, vegetables, and granola. On presentation, the rat was mildly dehydrated and had marked incisor malocclusion with enamel hypoplasia. On oral examination, the left mandibular molars were not visible and the gum line was prominent. Black punctate enamel discoloration was observed multifocally on molars, but no mucosal lesions were observed. The incisors were trimmed and the rat was discharged with analgesics, supportive care, and dietary recommendations. The rat's condition continued to deteriorate and, 1 wk later, a left mandibular mass appeared that the owner perceived as painful. Computed tomography of the head showed lysis of the body of the left mandible, absence of left mandibular molar teeth, and abnormal soft-tissue attenuation in the left tympanic bulla. On the last visit (Day 31), purulent discharge was visible in the left external ear canal and along the left mandibular gingiva. Fine-needle aspiration and cytology of the mandibular mass suggested a keratinizing epithelial tumor of benign appearance. Euthanasia was elected, based on the poor prognosis. Histopathological examination revealed a well-differentiated oral squamous cell carcinoma of the left mandibular region with ipsilateral subacute purulent otitis media. Key clinical message: Squamous cell carcinoma should be included in the differential diagnosis of an infected, non-ulcerated oral mass in a rat.

Canine lymphoma is the most common hematopoietic malignancy, but the primary mediastinal form is rare. Progression from this form to systemic multicentric lymphoma has not been clearly documented in veterinary medicine, and optimal treatment strategies remain uncertain. This report describes a case of primary mediastinal T-cell lymphoma in a young dog that progressed to multicentric disease and was managed with chemotherapy and radiation therapy. A 2-year-old castrated male Shetland sheepdog was referred for evaluation of a cranial mediastinal mass detected on thoracic radiographs. On physical examination, bradycardia was noted, with all peripheral lymph nodes within normal limits. Laboratory abnormalities included severe hypercalcemia, elevated symmetric dimethylarginine, and the presence of large lymphocytes on blood smear. Cytology, polymerase chain reaction for antigen receptor rearrangements, and flow cytometry confirmed CD4+ T-cell mediastinal lymphoma. Initial treatment with the 25-week L-CHOP protocol achieved complete remission, but relapse occurred at Week 8, prompting radiation therapy to the mediastinal and submandibular masses. These lesions regressed but generalized peripheral lymphadenomegaly and a splenic honeycomb pattern developed, indicating progression to multicentric lymphoma. Based on ex vivo drug sensitivity testing, lomustine was initiated as rescue chemotherapy, achieving a second complete remission. Nevertheless, relapse occurred 38 d after the initial lomustine administration, and the dog ultimately died. Key clinical message: This case highlights the fact that progression from primary mediastinal to multicentric lymphoma may be associated with a poor prognosis in dogs. Radiation therapy demonstrated potential efficacy and warrants further investigation as a treatment option for canine mediastinal lymphoma.

The majority of locally advanced esophageal squamous cell carcinoma (ESCC) patients do not achieve a pathological complete response (NPCR) after neoadjuvant chemoimmunotherapy (NCIT), and their prognosis exhibits significant heterogeneity. This study aimed to establish a pathological subtyping system for NPCR patients to guide precision adjuvant therapy.

Natural killer (NK) cells, critical components of innate immunity, possess the ability to eliminate tumor cells without prior sensitization. In gliomas, particularly glioblastoma, the tumor microenvironment (TME) exerts potent immunosuppressive effects that impair NK cell function through MHC-I overexpression, secretion of TGF-β and IDO, and recruitment of myeloid-derived suppressor cells (MDSCs). Emerging evidence highlights the significance of NK cell infiltration, cytotoxicity, and ligand-receptor dynamics-such as NKG2D, KIRs, and CX3CR1+ subsets-in shaping prognosis and therapeutic responsiveness in glioma patients. Therapeutic strategies including activation of NK cells via chemotherapeutics (bortezomib, decitabine), blockade of inhibitory receptors (NKG2A, CD161), and combinatorial approaches with immune checkpoint inhibitors are under active investigation. Notably, chimeric antigen receptor (CAR)-engineered NK cells targeting EGFR, HER2, GD2, and CD133 show promise in preclinical glioma models due to their enhanced specificity and reduced toxicity compared to CAR-T cells. This review summarizes the multifaceted roles of NK cells in glioma immunity and highlights novel immunotherapeutic strategies to restore NK cell function and improve clinical outcomes.