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Pleural mesothelioma (PM) is a rare and aggressive cancer with limited treatment options and poor prognosis. Unlike other thoracic cancers responding well to immunotherapy, PM typically lacks key predictive biomarkers such as Programmed Death-Ligand 1 (PD-L1) tumor expression. Nonetheless, immune checkpoint inhibitors (ICIs) have shown clinical activity in PM, particularly in non-epithelioid subtypes. However, only a subset of patients benefits from this approach, and resistance remains a major challenge. A growing body of evidence suggests that tumor microenvironment (TME) plays a central role in shaping this resistance. In PM, the TME is notably immunosuppressive, dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These elements act as a shield against immune activation, limiting the efficacy of ICIs. Novel therapeutic strategies aimed at depleting or modulating suppressive immune populations within the TME are emerging as promising avenues to overcome resistance and enhance the effectiveness of ICIs. In this narrative review, we examine the unique features of the TME in PM, its role in immunotherapy resistance, and emerging strategies aimed at harnessing or remodeling the TME to improve patient outcomes.

Small cell lung cancer (SCLC) is one of the deadliest types of lung cancer, with most cases being diagnosed at advanced stages. The gold standard approach in SCLC treatment has been chemotherapy, although it has been associated with limited efficacy and significant toxicity. In recent years, the integration of immunotherapies coupled with traditional chemotherapy has expanded the treatment landscape for SCLC. Nevertheless, a major challenge remains in accurately predicting which patients will benefit from these treatment strategies. However, the paucity of available tumor tissue in some patients requires the exploration of alternative approaches. In this context, liquid biopsy provides a minimally invasive tool for earlier diagnosis and treatment decision-making. Peripheral blood contains several tumor-derived elements, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and platelets, which provide real-time insights into the tumor, offering a dynamic alternative to traditional tissue biopsies. This article aims to comprehensively review the latest research on the application of liquid biopsy in SCLC. Specifically, the studies reviewed here focus on the detection, counting, and profiling of CTCs and the genomic, fragmentomic, and methylomic patterns of ctDNA across various patient cohorts and treatment settings. These studies reported promising results, particularly in the areas of early diagnosis and prognosis, suggesting that liquid biopsies could significantly enhance the management of SCLC patients. Additionally, emerging biomarkers such as serum/plasma-derived EV proteins and miRNA signatures, and the platelet-lymphocyte ratio have shown potential, however, their clinical application is still in the early stages. Although the findings regarding liquid biopsy-based markers are encouraging, their translation into the clinics is not yet achieved, mainly due to the low number and high variability of enrolled patients along with the lack of universal isolation strategies and univocal cut-offs for diagnosis and prognosis. Thus, large-scale, multi-institutional studies are essential to validate these markers and explore their integration into comprehensive multi-parameter scores. Finally, in-vitro/in-vivo CTC-derived cell lines/xenografts (CDX) might be used as pre-clinical "tumor-twin" models to understand SCLC biology as well as to test therapeutic options and comprehend the mechanisms of drug resistance, resulting in the expansion of alternative tools to improve precision medicine of this lethal neoplasm.

Background: Approximately 25–30% of non-small-cell lung cancer (NSCLC) patients are diagnosed when the disease is still resectable, although the risk of recurrence is significant. Recently, approaches based on targeted agents or immune checkpoint inhibitors (ICIs) have modified the management of such patients. However, some questions remain unanswered. Objectives: Our aim is to assess the current evidence on approaches involving targeted agents and ICIs in resectable NSCLC, to provide an up-to-date overview of the subject, and to identify areas of current debate, Methods: We analyzed randomized trials on ICIs and targeted therapies in early-stage NSCLC, published or presented at international oncology meetings throughout the last 5 years. Results: Osimertinib and alectinib have shown robust results in the adjuvant setting for molecularly identified patient subgroups, while ICIs have achieved robust data in the neoadjuvant/perioperative setting, with less consistent data on the pure adjuvant approach. Circulating tumor DNA levels may offer a possible biomarker for therapeutic decisions, albeit more prospective data are needed. Conclusions: Targeted agents and ICIs are revolutionizing early-stage NSCLC, similarly to what was observed in advanced disease. Prospective studies designed to compare neoadjuvant, adjuvant, and perioperative approaches and to assess the role of circulating biomarkers are warranted.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), although patient survival is still unsatisfactory. Accurate predictive markers capable of personalizing the treatment of patients with NSCLC are still lacking. Circulating extracellular vesicles involved in cell-to-cell communications through miRNAs (EV-miRs) transfer are promising markers. Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform, and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miRs (miR-181a-5p and miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased risk of mortality, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, and miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than 6 months. Our results demonstrate that EV-miRs are promising prognostic markers for NSCLC patients treated with nivolumab.

Background: Oncolytic viruses (OVs) have been utilized since 1990s for targeted cancer treatment. Our study examined the Measles–Mumps–Rubella (MMR) vaccine’s cancer-killing potency against Glioblastoma (GBM), a therapy-resistant, aggressive cancer type. Methodology: We used GBM cell lines, primary GBM cells, and normal mice microglial cells, to assess the MMR vaccine’s efficacy through cell viability, cell cycle analysis, intracellular viral load via RT-PCR, and Transmission Electron Microscopy (TEM). Results: After 72 h of MMR treatment, GBM cell lines and primary GBM cells exhibited significant viability reduction compared to untreated cells. Conversely, normal microglial cells showed only minor changes in viability and morphology. Intracellular viral load tests indicated GBM cells’ increased sensitivity to MMR viruses compared to normal cells. The cell cycle study also revealed measles and mumps viruses’ crucial role in cytopathic effects, with the rubella virus causing cell cycle arrest. Conclusion: Herein the reported results demonstrate the anti-cancer activity of the MMR vaccine against GBM cells. Accordingly, the MMR vaccine warrants further study as a potential new tool for GBM therapy and relapse prevention. Therapeutic potential of the MMR vaccine has been found to be promising in earlier studies as well.