The combination of enfortumab vedotin and pembrolizumab (EVP) has been recently approved for patients with locally advanced and metastatic urothelial carcinoma. This combination showed a higher objective response rate and superior progression-free survival and overall survival over traditional platinum-based chemotherapy in the frontline setting in the pivotal EV-302 trial. Despite the success, a subset of patients has primary refractory disease, and another subset will develop secondary resistance over time. Resistance to enfortumab vedotin may include the downregulation of nectin-4 expression to minimize antibody binding, upregulation of efflux pumps against the toxin, or direct resistance by the tubulin against the toxin. Resistance to pembrolizumab includes several methods to downregulate the immune system. Additionally, the type of histology of the urothelial carcinoma likely plays an important role in resisting EVP. This review summarizes these possible mechanisms of primary and secondary resistance, potential biomarkers predictive of response and resistance, and methods to overcome the resistance to EVP.

The purpose of this review was to provide a comprehensive review of the latest insights on the pathogenesis of uveal melanoma (UM) and its intracellular pathways. This article covers the epidemiology of UM, racial predispositions, cytogenetic and chromosomal alterations, gene mutations, key defective pathways, and their underlying mechanisms, as well as the application of hallmarks of cancer to UM. A key knowledge gap remains in identifying the most effective targeted therapy and determining the central pathway linking multiple signaling networks. UM is a malignant tumor arising from uveal melanocytes, predominantly affecting the choroid, with both genetic and epigenetic contributors. Key cytogenetic alterations include monosomy 3, chromosome 6p gain, chromosome 1p loss, and chromosome 8q gain. The most important UM-related signaling pathways are RAS/MAPK, PI3K/Akt/mTOR, Hippo-YAP, retinoblastoma (Rb), and p53 pathways. In the RAS/MAPK pathway, GNAQ/GNA11 mutations occur which account for more than 80% of UM cases. The PI3K/Akt/mTOR pathway promotes cyclin D1 overexpression and MDM2 upregulation, leading to p53 pathway inhibition. GNAQ/GNA11 mutations activate YAP via the Trio-RhoGTPase/RhoA/Rac1 signaling circuit in the Hippo-YAP pathway. Rb pathway dysregulation results from cyclin D1 overexpression or cyclin-dependent kinase inhibitor (CDKI) inactivation. In the p53 pathway, UM is characterized by p53 mutations, MDM2 overexpression, and Bcl-2 deregulation. Eventually, the ARF-MDM2 axis serves as a critical link between the RAS and p53 pathways. Hallmarks of cancer, such as evasion of growth suppression and self-sufficiency in growth signals, are also evident in UM. Genetic and epigenetic alterations, including NSB1, MDM2 and CCND1 amplification, and BAP1 mutations, play pivotal roles in UM pathobiology. Thus, UM exhibits a multifactorial pathology. By consolidating key mechanisms underlying UM pathogenesis, this review provides a comprehensive perspective on the involved pathways, offering insights that may facilitate the development of effective therapeutic strategies.

The combination of lenvatinib and pembrolizumab (Len + Pembro) demonstrated significant efficacy in the phase 3 CLEAR study for metastatic renal cell carcinoma (RCC). However, poor-risk patients represented only a small proportion of the trial population. This multicenter retrospective cohort study assessed the real-world efficacy and safety of Len + Pembro in patients with clear-cell metastatic RCC and intermediate or poor International Metastatic RCC Database Consortium risk. Outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Sixty patients were analyzed, with a median age of 56 years. Poor risk was identified in 53% of patients, and 90% had metastases to ≥ 2 organs. ORR was 48.33%, disease control rate was 86.7%, and median PFS was 19.0 months. Grade ≥ 3 adverse events occurred in 25% of patients, with 33.3% requiring lenvatinib dose reductions. Lenvatinib plus pembrolizumab demonstrated robust efficacy and a manageable safety profile in a real-world population with advanced disease and poor-risk features, consistent with outcomes reported in clinical trials.

Bladder cancer (BC) is a heterogeneous disease associated with high mortality if not diagnosed early. BC is classified into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), with MIBC linked to poor systemic therapy response and high recurrence rates. Current treatments include transurethral resection with Bacillus Calmette-Guérin (BCG) therapy for NMIBC and radical cystectomy with chemotherapy and/or immunotherapy for MIBC. The tumor microenvironment (TME) plays a critical role in cancer progression, metastasis, and therapeutic efficacy. A comprehensive understanding of the TME’s complex interactions holds substantial translational significance for developing innovative treatments. The TME can contribute to therapeutic resistance, particularly in immune checkpoint inhibitor (ICI) therapies, where resistance arises from tumor-intrinsic changes or extrinsic TME factors. Recent advancements in immunotherapy highlight the importance of translational research to address these challenges. Strategies to overcome resistance focus on remodeling the TME to transform immunologically “cold” tumors, which lack immune cell infiltration, into “hot” tumors that respond better to immunotherapy. These strategies involve disrupting cancer-microenvironment interactions, inhibiting angiogenesis, and modulating immune components to enhance anti-tumor responses. Key mechanisms include cytokine involvement [e.g., interleukin-6 (IL-6)], phenotypic alterations in macrophages and natural killer (NK) cells, and the plasticity of cancer-associated fibroblasts (CAFs). Identifying potential therapeutic targets within the TME can improve outcomes for MIBC patients. This review emphasizes the TME’s complexity and its impact on guiding novel therapeutic approaches, offering hope for better survival in MIBC.

Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, poses a significant therapeutic challenge due to its highly invasive nature and resistance to conventional therapies, including surgery, chemotherapy, and radiotherapy. Despite advances in standard treatments, patient survival remains limited, requiring the exploration of innovative strategies. Photodynamic therapy (PDT) has emerged as a promising approach, leveraging light-sensitive photosensitizers (PSs), molecular oxygen, and specific light wavelengths to generate reactive oxygen species (ROS) that selectively induce tumor cell death. Originally developed for skin cancer, PDT has evolved to target more complex malignancies, including GBM. The refinement of second- and third-generation PS, coupled with advancements in nanotechnology, has significantly improved PDT’s selectivity, bioavailability, and therapeutic efficacy. Moreover, the combination of PDT with chemotherapy, targeted therapy, and immunotherapy, among other therapeutic modalities, has shown potential in enhancing therapeutic outcomes. This review provides a comprehensive analysis of the preclinical and clinical applications of PDT in GBM, detailing its mechanisms of action, the evolution of PS, and novel combinatory strategies that optimize treatment efficacy. However, several challenges remain, including overcoming GBM-associated hypoxia, enhancing PS delivery across the blood-brain barrier, and mitigating tumor resistance mechanisms. The integration of PDT with molecular and genetic insight, alongside cutting-edge nanotechnology-based delivery systems, may revolutionize GBM treatment, offering new prospects for improved patient survival and quality of life.

Small cell lung cancer (SCLC) is an aggressive tumor characterized by early metastasis and resistance to treatment, making it a prime target for therapeutic investigation. The current standard of care for frontline treatment involves a combination of chemotherapeutic agents and immune checkpoint inhibitors (ICIs), though durability of response remains limited. The genetic heterogeneity of SCLC also complicates the development of new therapeutic options. Adoptive cell therapies show promise by targeting specific mutations in order to increase efficacy and minimize toxicity. There has been significant investigation in three therapeutic classes for application towards SCLC: antibody drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR)-T cell therapies. This review summarizes the recent advances and challenges in the development of adoptive cell therapies. Genetic targets such as delta-like ligand 3 (DLL3), trophoblast cell surface antigen 2 (Trop2), B7-H3 (CD276), gangliosides disialoganglioside GD2 (GD2) and ganglioside GM2 (GM2) have been found to be expressed in SCLC, which makes them prime targets for therapy development. While investigated therapies such as rovalpituzumab tesirine (Rova-T) have failed, several insights from these trials have led to the development of compelling new agents such as sacituzumab govitecan (SG), ifinatamab deruxtecan (I-DXd), tarlatamab, and DLL3-targeted CAR-T cells. Advancing development of molecular testing and improving targeted approaches remain integral to pushing forward the progress of adoptive cell therapies in SCLC.