Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in hematological malignancies but faces significant challenges in solid tumors due to the immunosuppressive and pro-oxidant tumor microenvironment (TME). Elevated levels of reactive oxygen species (ROS) in the TME-produced by both tumor and stromal cells-contribute to DNA damage, mitochondrial dysfunction, and altered signaling pathways in CAR-T cells, ultimately compromising their antitumor functions. Moreover, ROS act synergistically with other immunosuppressive mechanisms, further suppressing CAR-T cell activity. To circumvent these barriers, approaches such as genetic engineering to bolster antioxidant systems, metabolic reprogramming, CAR design optimization, and innovations including pharmacological or nanotechnology-based ROS scavenging strategies are being examined. This review comprehensively evaluates the mechanisms by which oxidative stress compromises CAR-T cell therapy in solid tumors and highlights redox-targeted interventions, providing critical insights to optimize therapeutic outcomes while maintaining physiological ROS balance.

Stereotactic radiosurgery has been explored as monotherapy or in combination with systemic agents in newly diagnosed and recurrent Glioblastoma (GBM). Data specific to Gamma Knife radiosurgery (GKSR) remains sparse, and its role is not clearly defined in guidelines. A systematic review and meta-analysis were conducted. Pubmed, Embase, and Web of Science were searched for articles reporting median progression-free survival (PFS) and overall survival (OS) times, actuarial survival, adverse events (AREs), and radionecrosis (RN) rates following salvage or adjuvant GKSR in GBM. Subgroup analyses were performed based on target delineation and treatment protocol. A total of 33 studies encompassing 1732 patients were included. In the recurrent (rGBM) cohort (n = 1082), the pooled median PFS was 5.6 months and OS 21.4 months, with an RN of 13 %. The addition of bevacizumab was associated with an extended median PFS of 7.9 months and OS of 25.7 months, along with a reduced rate of recurrence (9 %). Expanding the treatment field did not significantly affect PFS, OS, or RN rates. In the adjuvant setting (n = 647), GKSR achieved a median PFS of 9.4 months, OS of 18.3 months, and an RN rate of 13 %. Progression-free survival outcomes were broadly comparable to those of other salvage modalities and appeared to be further enhanced when combined with bevacizumab. While current evidence remains insufficient to support its routine use, GKSR may be considered an adjunctive component within individualized, multimodal treatment strategies, particularly when the therapeutic goal is to enhance local disease control with minimal added toxicity. PROSPERO ID: CRD420251072605.

This review explores the therapeutic potential of Antibody-Drug Conjugates (ADC) in urological malignancies, emphasizing treatment efficacy, safety, and future prospects. ADC selectively deliver cytotoxic agents to cancer cells, reducing off-target toxicity compared to conventional therapies. Comprising a monoclonal antibody (mAb) linked to a cytotoxic payload, ADC exert their effects through apoptosis, antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). This review highlights ADC advancements in urothelial cancer (UC), prostate cancer (PC), and renal cell carcinoma (RCC). Recent trials demonstrate encouraging outcomes with ADC such as Enfortumab Vedotin (EV), Sacituzumab Govitecan (SG), Trastuzumab Deruxtecan (T-DXd), and Disitamab Vedotin (DV) in UC, improving response rates and Progression-Free Survival (PFS). The influence of antigen expression, particularly Nectin-4 and Trop-2, on ADC treatment outcomes is investigated. In addition, efficacy and safety of ADC combinations with anti-PD-(L)1 therapies and dual immune checkpoint inhibitors to further enhance therapeutic benefit are explored. In PC, ADC targeting prostate-specific membrane antigen (PSMA), Trop-2, and B7-H3 exhibit promising antitumor activity, with research optimizing safety, efficacy, and monitoring strategies. In RCC, ADC against ENPP3, CD70, and TIM-1 show durable responses in early trials, though challenges such as dose-limiting toxicities require further investigation. Overall, this review underscores ADC as a transformative approach in uro-oncology, highlighting ongoing advancements in combination strategies and biomarker-driven applications to refine therapeutic outcomes and expand treatment options for these challenging malignancies.

HER2 is a transmembrane tyrosine kinase receptor involved in cell proliferation, survival, and differentiation. While its role in breast and gastric cancers is well established, increasing attention is being paid to HER2 expression in gynecologic malignancies. In endometrial cancer, HER2 overexpression is most commonly associated with serous endometrial carcinoma (SEC), where it occurs in approximately 30% of cases and correlates with poor prognosis, platinum resistance, and TP53 mutations. HER2-low expression, defined by IHC scores of 1+ or 2+ without gene amplification, has also emerged as a potential therapeutic target. Trastuzumab-based therapy has shown survival benefit in HER2-positive SEC, leading to its inclusion in current treatment guidelines. In ovarian cancer, HER2 amplification is most frequent in mucinous subtypes but also appears in clear cell and endometrioid carcinomas. The prognostic value remains debated, though recent trials of antibody-drug conjugates (e.g., T-DXd) show promise. In cervical cancer, HER2 is more commonly expressed in adenocarcinomas, particularly gastric-type variants, with gene amplification linked to adverse features. HER2 positivity is rare in vulvar and vaginal cancers but is notably present in extramammary Paget disease. Accurate HER2 testing relies on IHC with ISH confirmation and may be complemented by NGS or PCR in select cases. Diagnostic challenges include variable scoring systems, intratumoral heterogeneity, and HER2-low classification. Standardization of testing criteria and further clinical validation of HER2-targeted strategies across gynecologic tumors are essential to guide personalized therapy and improve outcomes.

Originally, breast cancer was not thought to be a very immunogenic malignancy. Recent research, however, has revealed that certain aggressive triple-negative breast tumors are immunogenic and demonstrate chemoresistance. In several cancer forms that are resistant to traditional treatments, including non-small cell lung cancer and melanoma, the discovery of immunotherapy via immune checkpoint blockage produced long-lasting results. Multiple additional cancer types have also seen notable improvements because of immunotherapy. But one of the malignancies that hasn't yet benefited from immunotherapy's surge is breast cancer (BC). When given as single-drug treatment or in conjunction with traditional therapies, PD1/PD-L1 pathway antagonists have shown encouraging outcomes in the evaluation of BC in the past few years, specifically in the triple-negative subtype, which has an aggressive profile and poor prognosis. Nevertheless, tumor cells can evade the immune system's activity by suppressing cytotoxic T cells through these checkpoint pathways. The T cells can start directly eliminating tumor cells and secreting immunostimulatory cytokines once they are awakened. The findings of the most current research assessing immune checkpoint inhibitors in BC will be presented in this review. In the present review study, we emphasize in PD-1/PD-L1 molecular mechanisms, upstream signaling pathways, clinical implications, and therapeutic potential in BC.

Chimeric antigen receptor (CAR) T-cell therapy utilizes synthetic biology techniques to engineer T cells to specifically target tumor cells using most commonly single-chain variable fragments (scFvs) to recognize tumor-associated antigens, which has been successfully applied to patients with B-lineage hematologic malignancies including leukemia, lymphoma and multiple myeloma. However, treatment outcomes for relapsed or refractory (R/R) T-cell malignancies remain suboptimal. A significant challenge is the shared antigens between malignant and normal T cells, leading to fratricide among CAR T cells. Moreover, the presence of malignant T cells in patients' leukapheresis may increase risk of relapse. Post-infusion, patients may experience severe T-cell aplasia, rendering the cancer patients who are generally immunocompromised even more immunodeficient. This review article explores CAR-based cellular therapy, including immune effector cells (IECs) such as conventional T cell subsets, natural killer (NK) cells, natural killer T (NKT) cells, cytokine-induced killer (CIK) cells, and γδ T cells for T-cell malignancies. We discuss multiple antigen-targeting, emerging technologies, and the latest clinical trials in attempt to improve CAR-based therapy for T-lineage neoplasms.

Breast cancer is a leading cause of cancer-related mortality in women worldwide. Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown efficacy in improving progression-free survival (PFS), particularly in patients with breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutations and homologous recombination deficiency (HRD).

Cancer remains one of the most biologically intricate and heterogeneous diseases, with variability spanning genetic, epigenetic, metabolic, spatial, and immunological dimensions. This multifactorial complexity is shaped by tumor-microenvironment interactions, immune modulation, clonal evolution, and therapeutic pressures, creating profound challenges for accurate prognosis, treatment selection, and durable response prediction. Conventional single-modality analytical approaches often capture only isolated features of this landscape, limiting their ability to generalize across patient populations and clinical settings. Selective multimodal deep learning (MDL) provides a transformative framework by mechanism-informed integration of complementary biomedical data-including genomics, transcriptomics, histopathology, medical imaging, proteomics, metabolomics, electronic health records (EHRs), and immunological profiles into unified models capable of capturing cross-scale dependencies and emergent patterns, while mitigating interference through targeted fusion strategies. The interpretability of these models is enhanced by explainable artificial intelligence (XAI), which translates complex computational predictions into transparent, biologically grounded explanations that align with known oncological and immunological processes. A distinctive focus of this review is immunology-informed integration, which connects predictive signatures to tumor-immune microenvironment dynamics, enhancing biomarker discovery, immunotherapy stratification, and hypothesis generation. We review key foundations, fusion strategies, and explainability methods in precision oncology, emphasizing rigorous validation frameworks that include statistical metrics and biological plausibility assessments. We address challenges such as data harmonization and modality imbalance, and discuss criteria for selecting modalities to ensure scientific validity. Finally, we outline future directions like federated learning for privacy, causal inference-driven explainability, and patient-specific digital twins, all aimed at advancing personalized precision oncology.

CD49d is a protein present on CLL cells that have been shown to be involved in pathological processes associated with this hematological malignancy. Although its prognostic significance has been shown before, new studies have emerged since. We performed a meta-analysis of studies aimed at determining the prognostic value of CD49d in CLL. We systematically searched three databases: PubMed, Web of Science, and Embase. Hazard ratios and corresponding confidence intervals for overall survival, treatment-free survival, and progression-free survival were extracted from selected studies and were pooled using random-effects models. Based on our search strategy, we retrieved a total of 562 records, with 19 being included in the final analysis, comprising 6457 patients. Results from meta-analysis showed high predictive value of CD49d in terms of OS, TFS, and PFS with estimated HR values of 2.28, 2.06, and 3.63, respectively. Heterogeneity estimation showed a lack of it in terms of OS, a low degree regarding PFS analysis, and moderate heterogeneity in terms of TFS. Our work provides evidence for the high quality of CD49d as a prognostic factor for clinical outcomes for CLL patients. It is highly suggestive that CD49d is able to distinguish patients with a higher risk of death, progression, or need for treatment without its dependence on other clinical factors, making it highly reliable in a clinical setting. It is necessary to assess its utility in the context of novel treatment options and determine the importance of bimodal expression of CD49d regarding prognostic value.

The prognostic significance of circulating biomarkers in appendiceal neoplasms remains inconsistent across studies, hindering their clinical implementation for prognostic stratification. This meta-analysis aims to estimate and compare the prognostic value of various circulating biomarkers in appendiceal neoplasms.

The acidification of the tumor microenvironment is a hallmark of malignant tumors, resulting from the coordinated action of multiple pH-regulating proteins.pH-regulating Key molecules, including the sodium-hydrogen exchanger (NHE), bicarbonate transporters, monocarboxylate transporters (MCTs), V-type ATPase (V-ATPase), and carbonic anhydrases (CAs) play central roles in tumor metabolic reprogramming and microenvironmental acidification. This review re-examines the Warburg effect and proposes that cytoplasmic alkalinization is the critical switch that initiates aerobic glycolysis and inhibits oxidative phosphorylation. The review further analyzes the roles of pH-regulating proteins in tumor migration, invasion, and therapeutic resistance, and summarizes therapeutic strategies targeting these proteins. Finally, the review outlines future directions for multi-target synergistic interventions and clinical translation, thereby providing a theoretical foundation for developing novel precision therapies that target tumor pH regulation.

The integration of chemotherapy with immune checkpoint inhibitors (ICIs) represents a transformative strategy in oncology, synergistically enhancing anti-tumor efficacy by combining cytotoxic effects with immune reactivation. However, the full potential of this combination is often limited by therapeutic resistance, immune-related adverse events, and a lack of predictive biomarkers. This review comprehensively examines the mechanistic basis, clinical applications, and current challenges of chemo-immunotherapy, with a particular emphasis on the emerging role of artificial intelligence (AI) in optimizing such combinations. We discuss how chemotherapy-induced immunogenic cell death (ICD), antigen release, and remodeling of the tumor microenvironment (TME) potentiate ICI efficacy. Furthermore, we explore how AI-driven approaches, including multi-omics integration, radiomics, and deep learning facilitate the identification of synergistic drug pairs, prediction of treatment responses, and stratification of patients. Despite promising clinical outcomes across various malignancies, key challenges such as chemotherapy-induced immunosuppression, tumor heterogeneity, and data interpretability remain. Ultimately, the convergence of AI with immuno-oncology holds great promise for advancing personalized cancer therapy through improved biomarker discovery, rational combination design, and dynamic treatment adaptation.

Because increasing evidence shows the anticancer potential of curcumin, a polyphenolic compound of Curcuma longa, this narrative review seeks to elucidate the preclinical evidence of curcumin for skin cancer, specifically melanoma and non-melanoma skin cancers. From the databases PubMed, Scopus, Web of Science, Embase, and Google Scholar, literature published between January 2018 and June 2025 was retrieved. The search was performed using the terms 'curcumin', 'skin cancer', 'melanoma', 'basal cell carcinoma', 'squamous cell carcinoma', and other relevant molecular terms. The search resulted in the retrieval of 15 original studies, which included the in vitro and in vivo studies, and which fulfilled the inclusion and exclusion criteria. Curcumin was shown to have anticancer activity through the modulation of the NF-κB, PI3K/AKT, JAK/STAT, and apoptotic networks (Bax, Bcl-2, and caspase-3). The strategies involving the use of PEGylated nanocarriers, folate-targeted nanoparticles, and chitosan films were suggested in literature to improve the curcumin solubility, bioavailability, and skin penetration. Some studies tried to investigate the combined use of curcumin and other agents, such as thymoquinone or HSV-TK/GCV gene therapy, which have synergistic effects in melanoma models. Nevertheless, preclinical studies have proposed very promising results, and to date, there have been no human clinical trials. Further research is needed to assess the safety, pharmacokinetics, and therapeutic potential of curcumin-based interventions in dermatologic oncology.

Histotripsy is a novel, non-thermal ultrasound-based technology that utilizes focused acoustic waves to mechanically destroy tumor tissue. This review examines histotripsy's potential to overcome immunoresistance and treat metastatic cancers by inducing potent innate and adaptive anti-tumor immune responses. Tumor destruction releases tumor-specific antigens and damage-associated molecular patterns, facilitating immune activation and transforming the tumor microenvironment from immunologically "cold" to "hot". Preclinical studies show increased CD8 + T cell infiltration, macrophage repolarization towards a pro-inflammatory phenotype, and both local and distant (abscopal) tumor regression. Clinically, patient trials in hepatic tumors report high procedural success and safety, with initial reports of abscopal responses suggesting significant potential systemic benefit. Histotripsy offers potential benefits over radiation therapy, which rarely induces a systemic response, and immune checkpoint inhibitors, which are associated with severe systemic adverse effects. Although further clinical validation is needed, accumulating evidence positions histotripsy as a promising advancement in minimally invasive, immunomodulatory cancer treatment.

Nectins and Nectin-like (Necl) proteins, a family of immunoglobulin-like cell adhesion molecules, are increasingly recognized for their dysregulated expression and aberrant functions in malignancies. They exert dual roles in cancer: promoting tumor progression (proliferation, invasion, metastasis, chemoresistance) through tumor-intrinsic and microenvironment-mediated mechanisms and facilitating immune evasion by engaging checkpoint receptors (TIGIT, CD96, PVRIG) on cytotoxic lymphocytes. Consequently, Nectins have emerged as critical therapeutic targets for modulating both tumor biology and the immune microenvironment. Recent therapeutic advances, particularly Nectin-4-targeted ADCs, anti-TIGIT ICIs, and bispecific antibodies (BsAbs), underscore their clinical promise. This review integrates current understanding of Nectin family members in oncogenesis and immunoregulation, focusing on their biological functions, mechanisms of immune modulation, therapeutic strategies, and remaining challenges in clinical translation.

The prognosis of neuroendocrine neoplasms (NENs) is traditionally driven by tumor grade, primary site, hormonal functionality, and disease staging; however, emerging evidence identifies tumor burden-encompassing the size, number, and anatomical spread of lesions-as an independent determinant of outcome. Despite its clinical relevance, tumor burden lacks a standardized definition across studies, with criteria ranging from liver involvement thresholds to metastatic site counts, extrahepatic spread, or surrogate biochemical markers, limiting cross-study comparability.

Major histocompatibility complex (MHC) molecules, as core mediators of antigen presentation in the immune system, play pivotal roles in activating anti-tumor immune responses by presenting antigens to CD8⁺ and CD4⁺ T cells. However, tumor cells and immunosuppressive cells within the tumor microenvironment (TME) employ multi-dimensional mechanisms to dysregulate MHC expression and function-including epigenetic silencing, autophagic degradation, and interference with transcription factors such as NLRC5 (for MHC-I) and CIITA (for MHC-II). These mechanisms enable immune escape and limit the efficacy of cancer immunotherapy. Additionally, we review MHC-based therapeutic strategies-such as cytokine therapy, TCR-T cell therapy, immune checkpoint inhibitor (ICI) combination therapy, and tumor vaccine therapies-that have been developed to restore MHC function and overcome immune escape. A deeper understanding of the regulatory networks governing MHC molecules in tumor immunity will provide critical insights for the development of precise and effective immunotherapeutic strategies, ultimately improving clinical outcomes for cancer patients.

Colorectal cancer with lung metastases (CRC-LM) pose a significant clinical challenge. Although systemic therapy is the mainstay, local control treatments (LAT), including surgery, stereotactic body radiation therapy (SBRT), and image-guided thermal ablation (IGTA), are increasingly utilized for oligometastatic disease. Previous studies have generally reported on surgery or SBRT; there are few reports on IGTA. This review aimed to synthesize evidence on the efficacy and outcomes of different LAT modalities for CRC-LM.

Brain metastasis poses a formidable barrier in cancer management, characterized by delayed diagnosis and limited treatment options. Extracellular vesicles (EVs), nano-sized, lipid bilayer-bound particles secreted by virtually all cell types, have emerged as dual-functional agents with potential to revolutionize both diagnosis and treatment. Owing to their ability to cross the blood-brain barrier and circulate in bodily fluids, EVs serve as non-invasive reservoirs of tumor-derived biomarkers, offering new avenues for early and accurate diagnosis. Simultaneously, advances in EV engineering have enabled their use as targeted therapeutic vehicles capable of delivering chemotherapeutics, nucleic acids, or immunomodulators directly to metastatic brain lesions. Functionalization with brain-targeting ligands further enhances their specificity, reducing systemic toxicity and improving therapeutic precision. This review systematically explores the mechanistic roles of EVs in brain metastasis progression and highlights their transformative potential as both diagnostic tools and therapeutic nanocarriers, breaking current barriers in the clinical management of brain metastases.

Prostate cancer (PCa) is a primary cause of male cancer death, underlining the crucial need for new therapies. Natural nanovesicles known as exosomes (EXOs) have shown great promise as therapeutic vectors due to their excellent biocompatibility, minimal immunogenicity, and inherent capacity to carry bioactive cargo. Different cell types may produce these vesicles, and each one imparts unique biological characteristics and therapeutic processes. This review compares the therapeutic potential of EXOs obtained from three primary sources for the treatment of PCa. The usefulness of mesenchymal stem cell-derived EXOs (MSC-EXOs), which leverage their inherent tumor tropism to serve as naturally occurring delivery vehicles for therapeutic agents, is critically examined. We investigate the potential of immune cell-derived EXOs (IC-EXOs) as cytotoxic agents or cell-free vaccines that effectively activate anti-tumor immunity. We also discuss the paradoxical role of tumor-derived EXOs (TEXs), which can serve as vaccine antigens or as tools for liquid biopsy, despite their role in cancer development. We highlight the unique benefits, drawbacks, and best therapeutic settings of these platforms by combining evidence from multiple platforms. Lastly, we address crucial clinical translation issues, such as manufacturing and standardization, and offer a framework for selecting the best EXO source in the evolving field of PCa treatment based on specific therapeutic goals.

Despite major gains with immunotherapy, many tumors remain non-responsive because of poor antigen release and a suppressive tumor microenvironment (TME). Oncolytic virotherapy (OVT) directly lyses cancer cells and secondarily inflames the TME via immunogenic cell death and type I interferon (IFN-I) signaling. Here we present primary clinical and preclinical evidence on (i) mechanisms that govern OV selectivity and immune priming, (ii) genetic engineering strategies linked to clinical signals, and (iii) translational lessons across species, with emphasis on companion-animal oncology as a bridge to human trials. We highlight trials where OVs prime checkpoint response (e.g., DNX-2401→pembrolizumab in recurrent glioblastoma) and where vector design (e.g., TK-deleted vaccinia, CG0070) or payloads (e.g., IFNβ, NIS) drive measurable benefit. We conclude with actionable priorities, patient selection by IFN-pathway competence, receptor-tropism panels, and rational OV-ICI sequencing, to accelerate durable responses.