Melanoma remains the deadliest form of skin cancer and continues to account for a disproportionate number of deaths worldwide. Although targeted therapies have markedly improved outcomes for subsets of patients, both de novo and acquired resistance remain major clinical challenges, particularly in tumors with restricted systemic therapeutic options. Central to melanoma progression, invasion, and metastasis is the tumor microenvironment (TME), which engages in dynamic and reciprocal crosstalk with melanoma cells across all disease stages. Here, we synthesize recent advances elucidating how non-immune components of the melanoma TME (including keratinocytes, fibroblasts, extracellular matrix, and adipocytes) mechanistically regulate tumor motility and local invasion. We highlight how biochemical, biomechanical, and metabolic cues cooperatively remodel melanoma invasive behavior. Finally, we review current clinical efforts targeting melanoma-TME interactions and discuss critical gaps that must be addressed to advance these strategies into durable clinical therapies.
Breast cancer remains a leading cause of cancer morbidity and mortality, representing the most frequently diagnosed new cancer of 2024. Despite overall improvements in survival, women of African ancestry experience disproportionately higher rates of aggressive subtypes and adverse outcomes, signifying persistent biological and clinical gaps. Mechanotransduction, the process by which cells sense and respond to mechanical cues, regulates mammary homeostasis, tumor progression, metastatic dissemination, and therapeutic response. However, its context-dependent and bidirectional roles remain incompletely resolved, and reproducing biomechanical environments in preclinical models remains a substantial challenge. This review synthesizes current understandings of canonical and cancer-associated mechanotransduction in breast tissue, including cell–extracellular matrix (ECM) and cell–cell adhesions, mechanosensitive ion channels, glycocalyx remodeling, cytoskeletal dynamics, nuclear force transmission, and mechanosensitive transcription. It further examines how ECM stiffness, viscoelasticity, ligand availability, collagen architecture, tensile and compressive stresses, and stromal and immune cell activity influence invasion, metastasis, and treatment resistance. Ancestry-associated stromal, molecular, and structural variations are considered as a critical motivation, but remain incompletely characterized as sources of ancestry-dependent heterogeneity. Thus, this review explores mechanotransduction as a framework for assessing proliferation and metastasis mechanisms through two-dimensional culture, three-dimensional matrices, spheroids, organoids, co-cultures, bioreactors, organ-on-a-chip systems, bioprinting, animal models, and computational approaches for their capacity to reproduce these processes. We ultimately propose an iterative design–build–validate framework that links empirically derived mechanical and molecular measurements to model selection, construction, and multilevel validation. Integrating mechanobiological heterogeneity into rigorously benchmarked models could improve understanding of metastatic progression, reveal context-dependent therapeutic resistance, and support more representative and patient-informed breast cancer research.
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have transformed cancer treatment, but durable benefit and immune-related adverse events (irAEs) remain difficult to predict. Germline single nucleotide polymorphisms (SNPs) in PDCD1, CD274, and PDCD1LG2 may influence checkpoint expression and immune-cell function. This narrative review integrates clinical association studies with available mechanistic evidence and evaluates effect estimates, endpoint definitions, replication, ancestry, and functional support. The leading candidates are PDCD1 rs7421861 for survival outcomes, PDCD1 rs10204525 for irAEs, CD274 rs822336 for response and survival, and CD274 rs822339 and rs1411262 for survival. However, most cohorts are small and retrospective, allele coding is not always harmonized, and genotype-by-treatment interaction analyses are uncommon. No variant has therefore been validated for routine clinical use. Future studies should use prespecified endpoints and genetic models, adjusted estimates with 95
Nicotinamide adenine dinucleotide (NAD+) functions in cancer as a compartmentalized signaling currency, coupling tumor cell fitness to immune competence within the tumor microenvironment (TME). In malignant cells, NAD+ sustains redox balance, poly(ADP-ribose) polymerase (PARP)-dependent DNA repair, sirtuin-mediated chromatin remodeling, and metabolic stress adaptation. In immune effector cells, the same metabolite governs mitochondrial integrity, effector persistence, and resistance to exhaustion. This duality is the basis of the explanation advanced here for why first-generation inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting salvage pathway enzyme, failed clinically when deployed as cytotoxic monotherapies without an immunometabolic rationale. This review synthesizes the field around a central premise: NAD+ operates as a context-dependent metabolic immune checkpoint whose therapeutic value depends on where in the tumor immune ecosystem the pathway is perturbed and whether checkpoint blockade is deployed concurrently. The therapeutic landscape is reorganized around five pharmacological classes, which differ in how far each has been tested: (i) NAMPT catalytic inhibitors, evaluated clinically and withdrawn; (ii) bifunctional NAMPT/programmed death-ligand (PD-L1) compounds and proteolysis-targeting chimera (PROTAC)-mediated NAMPT degradation, both preclinical; (iii) NAD+ precursor-based immunorestorative strategies, including ex vivo rescue of age-associated chimeric antigen receptor T (CAR-T) cell dysfunction through NMN/CD38 inhibitor combinations; (iv) adenosinergic axis targeting, in which anti-CD38 and anti-CD73 agents are approved or in trials while the proposed triple-blockade of CD38, CD73, and PD-1/PD-L1 remains untested; and (v) combinations with PARP and indoleamine 2,3-dioxygenase (IDO) inhibitors, which rest on mechanistic rationale. A tripartite pharmacological taxonomy distinguishes intracellular (iNAMPT), extracellular (eNAMPT), and vesicle-associated (vNAMPT) NAMPT as discrete drug targets. The analyses examines how TME acidification, precursor competition, and extracellular NAD+ catabolism through the CD38–CD203a–CD73 noncanonical adenosine axis reshape immune fitness, and why biomarker-guided separation of tumor-directed NAD+ depletion from immune-directed NAD+ restoration is required for rational clinical translation. Throughout, findings that are experimentally established are separated from those that remain contested or hypothetical, and the criteria under which the checkpoint designation is analytically useful, together with the conditions under which it is not, are stated explicitly.
Mesothelioma is characterized by extreme cellular plasticity, profound stromal remodeling, and near-universal resistance to therapy. While epithelial-mesenchymal transition (EMT) has long been implicated in disease progression, mesothelioma arises within a uniquely heterogeneous cellular ecosystem in which multiple non-epithelial lineages contribute to mesenchymal states. Here, we introduce cross-lineage mesenchymal transition (XMT) as a unifying framework describing the convergence of epithelial, mesothelial, endothelial, immune, hematopoietic, adipocytic, neural, and stem-like cells toward fibroblast-like, extracellular-matrix-producing phenotypes. Mesothelioma is presented as a conceptual framework for studying convergent mesenchymal programming and XMT-related processes, rather than as a definitively proven example of XMT. XMT is driven by shared signaling axes, including TGF-β, Wnt/β-catenin, Notch, hypoxia, and mechanotransduction pathways that erase lineage identity and reinforce mesenchymal programs. Recurrent mesothelioma-associated genomic alterations, particularly loss of BAP1 and CDKN2A, further potentiate XMT by reshaping chromatin accessibility, cell cycle control, metabolic state, and inflammatory signaling, thereby lowering barriers to lineage plasticity. Integrative bulk and single-cell transcriptomic analyses reveal that XMT-associated gene signatures correlate with stromal enrichment, immunosuppressive myeloid and regulatory T cell infiltration, and poor survival in patients with pleural mesothelioma. XMT underlies mesothelioma desmoplasia, immune evasion, and therapy resistance, and represents a tractable vulnerability for stromal, immune, and plasticity-directed therapeutic strategies. Framing mesothelioma through the lens of XMT provides a unifying biological rationale for stromal evolution and identifies actionable pathways-genetic, epigenetic, and microenvironmental mechanisms that may be targeted to overcome plasticity-driven disease progression. This review highlights specific therapeutic strategies, including stromal-targeted approaches aimed at TGF-β signaling and extracellular matrix remodeling, immune-targeted approaches that address myeloid-driven immunosuppression and inflammatory signaling, and plasticity-directed strategies targeting EMT/stemness programs and cellular state transitions.
