Search Results (330)

Prostate cancer (PCa) is the leading cause of cancer-related deaths worldwide and the second most common cancer among men. Treatment options depend on factors like age, androgen sensitivity, PSA levels, Gleason score, TNM stage, and recurrence risk. Available treatments include hormonal therapy, radiation, surgery, and chemotherapy. Early immunological treatments were limited by poor lymphocyte infiltration and an immunosuppressive environment. Today, strategies such as dendritic cell vaccines, immune checkpoint inhibitors (ICIs), and adoptive cell therapy (ACT) are used. ACT, especially CAR T-cell strategies, aims to overcome traditional treatment limitations, particularly in advanced and metastatic castration-resistant prostate cancer (mCRPC), though it remains in early development. Personalized medicine uses molecular insights from the diseased tissue to tailor treatments. Variability in patient response, due to tumor heterogeneity and prior treatments, highlights the importance of personalized and combination therapies as future strategies for effective immunotherapy. This review explores the current landscape of PCa. We analyze treatment guidelines established by NCCN and EANM-ESTRO-ESUR-ISUP-SIOG. We comprehensively examine immunotherapeutic strategies currently available or under investigation for prostate cancer, with particular emphasis on ICIs, ACT with a focus on CAR T-cell therapy, combination approaches and therapeutic synergies, and predictive biomarkers of immunotherapy response. Additionally, we discuss the challenges and future directions in the implementation of immunotherapy for the management of prostate cancer. Full article

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

Copper (Cu) is an essential element required by all living cells, where it supports critical enzymatic and signaling functions. In cancer, this balance is often disrupted, creating vulnerabilities that can be therapeutically exploited. Changes in Cu availability have been shown to influence key immunoregulatory pathways, including those involved in inflammation, cell death, and immune evasion. Notably, Cu can drive expression of programmed death ligand 1 (PD-L1), contributing to immunosuppression, while also promoting immunogenic cell death, which stimulates adaptive immune responses. These dual effects highlight the complexity and therapeutic potential of Cu-based interventions, particularly in the context of immune modulation and toxicity. This review argues that Cu-based nanomedicines can selectively deliver high concentrations of bioactive Cu to tumor cells, inducing cell death and triggering adaptive immune responses. We summarize current knowledge on Cu’s roles in cancer and immunity, emphasizing recent insights into how these intersect through Cu-mediated modulation of anticancer immune pathways. Finally, we explore the clinical potential of Cu-based nanomedicines to convert immunologically “cold” tumors into “hot” ones, thereby improving responses to immunotherapy. Realizing this potential will depend on the thoughtful integration of Cu delivery approaches with existing immunotherapeutic strategies. Full article

Background: Oncological treatment remains a major clinical challenge. Despite therapeutic advances and the diversity of available approaches, many tumors continue to exhibit limited responsiveness to chemotherapy. In this context, nutrition has emerged as a promising complementary strategy to support cancer therapy. In particular, interventions based on nutritional deprivation have gained prominence due to their ability to modulate tumor metabolism, inducing alterations that may increase the sensitivity of cancer cells to conventional treatments. Accordingly, the present study aimed to evaluate the safety and efficacy of caloric restriction combined with chemotherapy in a Sarcoma-180 model, investigating its effects on immunological and hematological parameters, antioxidant activity, oxidative stress, and tumor and liver morphology, as well as DNA damage. Methods: Mice bearing Sarcoma-180 were randomly assigned to four groups: Ad Libitum (AL), Ad Libitum + Doxorubicin (ALDOX), Caloric Restriction (CR), and Caloric Restriction + Doxorubicin (CRDOX). Assessment included tumor weight and volume, food and caloric intake, hematotoxicity, lipid metabolism, oxidative stress and antioxidant markers, genotoxicity, morphological alterations in the tumor and liver, and overall survival. Results: The data obtained demonstrate that caloric restriction combined with doxorubicin is both safe and feasible, as it preserves body weight and does not induce metabolic disturbances. Importantly, this combined strategy produced a marked reduction in tumor volume and mass while also mitigating the hematotoxicity typically associated with doxorubicin. In peripheral blood, the regimen decreased chemotherapy-induced DNA damage, supporting a systemic protective effect. Consistently, the combination reduced oxidative stress markers (NOx and MDA) and enhanced antioxidant activity within the tumor. Histological analyses further confirmed these outcomes, showing tumor cell death with features compatible with apoptosis and reduced local invasion. Together, these data indicate that caloric restriction enhances the antitumor efficacy of doxorubicin while simultaneously improving treatment tolerance. Conclusions: This study demonstrates that caloric restriction, combined with doxorubicin, is safe, well-tolerated, and enhances the antitumor response in the Sarcoma-180 model. Full article

(1) Background: The clinical course of acute myocarditis in adolescents is heterogeneous, and reliable predictors of early functional changes remain limited, particularly in patients without severe systolic dysfunction. Routine hematologic parameters may reflect the early inflammatory response, but their prognostic relevance in pediatric non-fulminant myocarditis is poorly defined. This exploratory study aimed to assess whether admission inflammatory blood indices are associated with short-term changes in left ventricular systolic function in adolescents with acute myocarditis. (2) Methods: We retrospectively analyzed 44 adolescents (median age 16 years, 84% male) hospitalized with suspected acute non-fulminant myocarditis between 2020 and 2023. All patients had preserved or mildly reduced left ventricular ejection fraction (LVEF) at presentation. Clinical, laboratory, electrocardiographic, and echocardiographic data obtained at admission were analyzed. Changes in LVEF between the acute and post-acute phases during hospitalization were assessed using transthoracic echocardiography. Cardiac magnetic resonance imaging was performed in a subset of patients to support diagnosis but was not uniformly available for quantitative analysis. (3) Results: No in-hospital deaths occurred. A modest positive correlation was observed between neutrophil count at admission and improvement in LVEF during hospitalization (r = 0.348, p = 0.028). No significant associations were found between LVEF change and white blood cell count, lymphocyte count, monocyte count, neutrophil-to-lymphocyte ratio (NLR), troponin I, or NT-proBNP. (4) Conclusions: In adolescents with non-fulminant acute myocarditis and preserved or mildly reduced systolic function, admission neutrophil count was associated with short-term improvement in left ventricular ejection fraction. Given the retrospective design, limited sample size, and absence of mechanistic data, these findings should be interpreted as hypothesis-generating. Further prospective studies incorporating standardized cardiac magnetic resonance imaging and immunologic profiling are needed to clarify the clinical significance of this association. Full article

Breast cancer is the most frequent gynecological malignancy and the main cause of cancer death in the female population worldwide. One of the most significant challenges in its clinical management is the molecular heterogeneity of malignant breast tumors, which is reflected in the current molecular classification of these entities. In each of these tumor molecular subtypes, distinct genetic alterations are involved, and several intracellular signaling pathways contribute to defining their biological identity and clinical response. This literature review summarized the main classic and emerging biomarkers in breast cancer, along with the therapies associated with them. There are several classic biomarkers associated with this disease, such as estrogen and progesterone receptors, the HER2 receptor, and the Ki-67 cell proliferation marker. Given the limitations of these biomarkers, new biomarkers have been identified, including the TP53 tumor suppressor gene, the EGFR, different types of RNAs, plus epigenetic and immunological biomarkers. The integration of classic and emerging biomarkers along with new therapeutic targets in the clinical practice has promoted a thorough understanding of the high molecular complexity of breast cancer and the development of precision medicine strategies which increase the chances of therapeutic success. Full article

Prostate cancer remains a leading cause of cancer-related mortality and castration-resistant prostate cancer (CRPC) is a critical therapeutic challenge. This review establishes a conceptual framework analyzing ferroptosis vulnerability through two principles: “robustness through redundancy” in defense systems and the “evolutionary arms race” between androgen receptor (AR) signaling and oxidative resistance. We traced the evolutionary trajectory of hormone-sensitive diseases, where the AR coordinates ferroptosis defenses via SLC7A11, MBOAT2, and PEX10 regulation through progressive adaptations: AR-V7 splice variants that maintain defense independently of androgens, AR amplification conferring hypersensitivity, and AR-independent JMJD6-ATF4 bypass in SPOP-mutated tumors. This transforms ferroptosis from a static vulnerability to a stage-specific strategy. Novel approaches include menadione-based VPS34 targeting, which induces triaptosis through an oxidative endosomal catastrophe. We categorized the rational combinations mechanistically as vertical inhibition (multi-step targeting of single pathways), horizontal inhibition (synthetic lethality across parallel defenses), and vulnerability induction (creating exploitable dependencies). Ferroptosis-induced immunogenic cell death enables synergy with checkpoint inhibitors, potentially transforming immunologically “cold” prostate tumors. This review establishes ferroptosis targeting as a precision medicine paradigm exploiting the tension between the oxidative requirements of cancer cells and their evolved, yet architecturally vulnerable, defense systems, providing a framework for stage-specific, biomarker-guided interventions. Full article

Radiotherapy remains a central component of cancer therapy that induces DNA damage and cancer cell death. Beyond its cytotoxic effects, radiotherapy acts as a potent immunomodulator by releasing immunogenic molecules, inflammatory mediators, and neoantigens that shape anti-tumor immunity. Radiation-induced immune responses can have opposing effects, including immune activation or immunosuppression that dictate local tumor responses. Increasing evidence suggests these immunologic effects are not confined to the site of irradiation, as radiation exposure to surrounding normal tissue can trigger systemic immune signaling that affects local tumor progression as well as metastatic spread. This review examines radiotherapy-induced immune responses across three interconnected contexts: (i) tumor-intrinsic signaling during radiation; (ii) tumor microenvironmental changes where innate and adaptive immune responses alter local outcomes; and (iii) systemic and off-target effects contributing to broader immune remodeling. A comprehensive understanding of radiotherapy-induced immune responses will guide therapeutic strategies to enhance its immunological potential while minimizing unintended immune and off-target effects. Full article

Breast cancer remains the most prevalent malignancy among women worldwide, with hormone receptor-positive (HR+) tumors comprising approximately 70% of cases. Traditionally, HR+ breast cancer has been classified as immunologically “cold” due to its low PD-L1 expression, reduced tumor-infiltrating lymphocytes, and low tumor mutational burden, collectively limiting immunotherapy responsiveness. However, emerging evidence indicates significant molecular heterogeneity within HR+ tumors, characterized by specific genetic signatures and features of the tumor microenvironment (TME) that can be therapeutically reprogramed through chemotherapy-induced immunogenic cell death combined with immune checkpoint inhibition. Recent clinical trials demonstrate that biomarker-selected immune-enriched HR+ subsets, identified by MammaPrint Ultra-High 2 classification, homologous recombination deficiency, or elevated tumor-infiltrating lymphocytes, achieve notable pathological complete response rates with immune checkpoint inhibitor combinations. This review summarizes the dynamic interactions between genetic determinants and TME plasticity in HR+ breast cancer and critically assesses combination strategies across 31 neoadjuvant trials. We demonstrate that optimal efficacy requires biomarker-guided patient selection integrating genetic and TME features, precise sequencing, and a mechanistic understanding of drug-specific immunomodulatory effects. The integration of platform trial designs (I-SPY2, CheckMate-7FL) with composite biomarker algorithms represents a paradigm shift toward precision neoadjuvant immunotherapy, offering a conceptual framework for transforming outcomes in molecularly defined HR+ breast cancer subsets. Full article

Agriculture is still at serious risk from viral infections, particularly in light of climate change and more intensive farming practices. Small non-coding RNAs (sRNAs), in particular microRNAs (miRNAs) and circular RNAs (circRNAs), have emerged as crucial post-transcriptional regulators of plant antiviral defense in this setting. These molecules provide an essential RNA-based immunity layer by regulating hormones, autophagy, redox balance, immunological signaling, and programmed cell death. In this work, we examine the molecular processes through which circRNAs and miRNAs function during viral infection, focusing on how they affect autophagy and systemic acquired resistance (SAR). Through thorough searches of PubMed, Web of Science, and Scopus, we combined findings from peer-reviewed experimental and transcriptomic studies. Our study covers important crops as well as model species (Arabidopsis thaliana, Nicotiana benthamiana), providing a thorough understanding of sRNA synthesis, target control, and antiviral signaling. By combining previously disparate data, this review provides a coherent framework for understanding how short RNAs affect plant immune responses to viral infections. We highlight key regulatory relationships that need further study and propose that these results can be used as a foundation for new RNA-based biotechnological approaches. By carefully altering RNA regulatory mechanisms, scientists can use this information to help them create more resistant crops. Full article

The controlled pro-inflammatory immune response is critical for fighting against external and endogenous threats, such as microbes/pathogens, allergens, xenobiotics, various antigens, and dying host cells and their mediators (DNA, RNA, and nuclear proteins) released into the circulation and cytosol (PAMPs, MAMPs, and DAMPs). Several pattern recognition receptors (PRRs) and their downstream adaptor molecules, expressed by innate and adaptive immune cells, are critical in generating the inflammatory immune response by recognizing PAMPs, MAMPs, and DAMPs. However, their dysregulation may predispose the host to develop inflammation-associated organ damage, neurodegeneration, autoimmunity, cancer, and even death due to the absence of the inflammation resolution phase. The cytosolic calcium (Ca²⁺) level regulates the survival, proliferation, and immunological functions of immune cells. Cysteine-rich proteases, specifically calpains, are Ca²⁺-dependent proteases that become activated during inflammatory conditions, playing a critical role in the inflammatory process and associated organ damage. Therefore, this article discusses the expression and function of calpain-1 and calpain-2 (ubiquitous calpains) in various innate (epithelial, endothelial, dendritic, mast, and NK cells, as well as macrophages) and adaptive (T and B cells) immune cells, affecting inflammation and immune regulation. As inflammatory diseases are on the rise due to several factors, such as environment, lifestyle, and an aging population, we must not just investigate but strive for a deeper understanding of the inflammation and immunoregulation under the calpain system (calpain-1 and calpain-2 and their endogenous negative regulator calpastatin) lens, which is ubiquitous and senses cytosolic Ca²⁺ changes to impact immune response. Full article

Chronic hepatitis B virus (HBV) infection is a major health problem that leads to approximately one million deaths every year worldwide. Mother-to-child transmission (MTCT) is the major cause of chronic HBV infection. HBV e antigen (HBeAg) is a secretory viral protein and modulates the immunological landscape of the newborn to promote HBV persistence. HBeAg actively reprograms innate and adaptive immunity. Mechanistically, HBeAg regulates macrophage polarization, suppresses dendritic cell and natural killer (NK) cell activities, impairs T cell and B cell functions, and promotes the expansion of myeloid-derived suppressor cells (MDSCs). These multifaceted effects contribute to immune tolerance and persistent HBV infection in the offspring of carrier mothers. Clinically, HBeAg status is a critical determinant for MTCT risk stratification and intervention, particularly in resource-limited settings. Despite advances in neonatal immunoprophylaxis and maternal antiviral therapy, residual transmission of HBV persists. Emerging approaches targeting HBeAg directly or restoring antiviral immunity offer promising avenues for breaking immune tolerance and achieving HBV elimination. This review summarizes current understanding of HBeAg-mediated immune modulation and highlights strategies that are being used to disrupt MTCT and treat HBV patients. Full article

Background and Aim: People with HIV (PWH) have historically been excluded from cancer immunotherapy trials due to concerns over immune dysregulation and safety. This systematic review evaluates the safety, efficacy, and immunologic outcomes of Programmed death-1 (PD-1) inhibitors in PWH diagnosed with non-small-cell lung cancer (NSCLC). Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, Web of Science, and Medline through January 2025. Studies were included if they reported outcomes of ICIs in PWH with NSCLC. Data extraction included progression-free survival (PFS), overall survival (OS), immune-related adverse events (irAEs), antitumor response, HIV viral control, and immunologic parameters. Study quality was assessed using the Joanna Briggs Institute (JBI) checklist. Results: Six cohort studies (n = 762 patients) met inclusion criteria. ICIs used included nivolumab, pembrolizumab, atezolizumab, and durvalumab, with treatment durations ranging from 3.1 to 5.4 months. Median PFS ranged from 3.0 to 6.3 months, and OS ranged from 10.0 to 66.0 months. Overall response rates (ORRs) varied from 13% to 75%, and disease control rates (DCRs) ranged from 47% to 62.5%. irAEs occurred in 25% to 75% of patients, with 6–20% experiencing grade 3–4 events. Corticosteroids were required in 13–29% of patients, and treatment discontinuation due to toxicity occurred in up to 30%. Most patients had controlled HIV, with CD4 counts typically above 300 cells/μL and undetectable viral loads. Conclusions: ICIs appear safe and effective in PWH with NSCLC, with toxicity and efficacy outcomes comparable to the general population. While immunotherapy should not be withheld based solely on HIV status, better standardization in reporting HIV-related variables is needed to optimize patient selection and management. Full article

Background: Permanent cancer resolution requires a complete immunological response with generation of memory against malignant cells. Immunogenic cell death (ICD) achieves this by coupling cell death with the emission of damage-associated molecular patterns (DAMPs). Current cancer treatments immunosuppress the host; thus, new alternatives are needed. Ganoderma species produce anticancer triterpenoids (GTs); however, their mechanism remains unclear. Objective: This systematic review aims to provide insights into GTs’ pharmacodynamics and assess hypothetical ICD potential. Methods: Web of Science and PubMed databases were consulted following PRISMA guidelines. Studies from inception until 2024, reporting molecular changes associated with GTs’ anticancer effects, were considered. Nonhuman models were excluded. GTs and GTs-ICD converging molecular targets were listed and submitted to Cytoscape’s stringApp to construct protein interaction networks. Topological and enrichment analysis were performed. Results: A total of 204 articles were found, and 69 remained after screening. Overall anticancer effects include loss of mitochondrial membrane potential, DNA and RNA damage, autophagy, cell cycle arrest, and leukocyte activation. 136 molecular targets of GTs were identified; upregulated proteins include CHOP, PERK, p-eIF2α, and HSP70, a key DAMP. GTs and ICD share 24 molecular targets. GO:BP and KEGG enrichment analysis suggest that GTs’ anticancer effects are related to stress response, cell death regulation, and PD-L1/PD-1 checkpoint inhibition. GT-ICD enrichment converges on endoplasmic reticulum stress, unfolded protein response, and organelle membrane perforation. Conclusions: GTs exhibit polypharmacological anticancer effects, including anti-immunosuppression, upregulation of ICD-adjacent machinery, and even an increase in HSP. However, further studies are required to confirm a proper causal link between GTs’ cancer cell treatment and DAMP emission. Full article

Background: Endometriosis, believed by many to be rooted in immunology, is a chronic disease. Upregulation of programmed cell death protein 1 (PD-1) in immune cells may compromise their defensive function, a mechanism demonstrated in the context of cancer spread. This study aims to explore the potential involvement of PD-1 in the pathophysiology and progression of endometriosis. A total of 62 patients who underwent laparoscopic surgery were analyzed, with 47 diagnosed with endometriosis and 15 serving as controls. We collected peritoneal fluid and peripheral blood samples during surgery and examined them using flow cytometry. Using a panel of monoclonal antibodies, the samples were stained and the expression of PD-1 in immune cells was evaluated. Results: We observed a statistically significant rise in the percentage of the CD56⁺ CD16⁺ NK cell subset expressing PD-1 within the peritoneal fluid of endometriosis patients compared to the control group (p = 0.021). Similarly, we found that PD-1 expression on immune cells significantly differed based on factors such as body mass index and smoking habits. Moreover, peritoneal subsets of PD-1⁺ T and NK cells showed an increase in patients presenting symptomatic endometriosis and those with more widespread disease. Conclusions: Our evaluation of the inhibitory PD-1 receptor has strengthened the potential connection between immune escape mechanisms often seen in cancer cells and those in endometriotic cells. This concept could pave the way for future research in the field of immunomodulation and endometriosis. Full article