Skp2 at the crossroads of proliferation and immune evasion: a new target in the tumor microenvironment

The tumour microenvironment (TME) encompasses the dynamic interplay of malignant cells with surrounding stroma, vasculature, immune cells, and extracellular matrix. Decades of work have shown that the TME is far from a passive by-stander in oncogenesis; rather, it actively shapes tumour evolution, metastatic dissemination, and therapeutic responses [1, 2]. Immune infiltration—particularly of CD8⁺ T cells—is a favourable prognostic marker in many cancers, but this benefit can be erased by co-existent regulatory T-cells (Tregs), tumour-associated macrophages, myeloid-derived suppressor cells, and up-regulation of immune checkpoint molecules e.g. programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), V-domain immunoglobulin suppressor of T cell activation (VISTA). Collectively, these constitute an immunosuppressive TME [1, 2]. This arises from a convergence of tumour-intrinsic and host factors that blunt immune recognition and cytotoxic responses. Among several molecular circuits, neoangiogenic vasculature expresses aberrant adhesion molecules and may selectively favour Treg infiltration or exclude cytotoxic T-cells. For instance, prostate-specific membrane antigen expression in tumour neovasculature correlates with features of immune suppression (reduced cytotoxic T-cell signatures), suggesting that vascular phenotype can reflect and contribute to an immunosuppressive microenvironment [3]. This underscores how distinct molecular markers can reflect broader immune-landscape states.