MedComm (2020). 2026 Oct 4;7(10):e71040. doi: 10.1002/mco2.71040. eCollection 2026 Oct.
ABSTRACT
Immune-cell dynamics within the tumor microenvironment (TME) determine whether immune cells can reach, recognize, and sustain antitumor function against malignant cells under suppressive pressure. These dynamics are shaped by hypoxia, nutrient stress, cytokine and chemokine signaling, stromal architecture, vascular access, and multicellular crosstalk, and are further regulated by transcriptional and epigenetic programs. In this review, we organize TME immunity around four major barriers to effective therapy: failed immune access, defective antigen visibility and priming, failure to sustain effector function, and suppressive tissue remodeling. We use FOSL2/Fra-2, a component of activator protein-1 (AP-1) transcription factor complexes, as an example of how local signals can produce distinct regulatory effects in malignant, immune, and stromal compartments. FOSL2-associated programs have been linked to differentiation, plasticity, myeloid and stromal remodeling, stress adaptation, and selected immune-regulatory processes; however, the strength and direction of these associations vary by lineage, tumor type, model system, and level of functional evidence. We distinguish perturbation-supported mechanisms from correlative state signatures and identify the need for spatial validation, functional perturbation, and biomarker validation. This perspective supports biomarker-guided TME-directed therapy matched to the dominant immune barrier.
PMID:42830947 | PMC:PMC13634179 | DOI:10.1002/mco2.71040