Tumour microenvironment (TME)
A tumour is not just cancer cells. It is a neighbourhood of fibroblasts, immune cells, blood vessels, nerves, and scaffolding that the cancer recruits and corrupts, and that decides whether drugs and immune cells can get in.
Cancer-associated fibroblasts (CAFs; myCAF/iCAF/apCAF subtypes) build desmoplastic stroma and secrete TGF-β, CXCL12, and IL-6; tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) suppress T cells; regulatory T cells and exhausted CD8 T cells define immune phenotypes (inflamed, excluded, desert); abnormal vasculature creates hypoxia and blocks drug delivery; extracellular matrix stiffness signals through integrins and YAP; nerves and adipocytes add fuel and signals. Single-cell and spatial profiling has turned the TME from a concept into a map with druggable niches (FAP, CSF1R, CXCR4, TGF-β, adenosine).
In one picture
A castle under siege from the inside: the cancer conscripts the town's builders (fibroblasts) to raise walls, bribes the guards (macrophages) to look away, and diverts the water supply (vessels) so that reinforcements (T cells, drugs) never arrive.
Diagram
top- Checkpoint blockade (PD-1, CTLA-4, LAG-3) releases exhausted T cells
- Anti-VEGF normalises vessels and improves infiltration
- FAP-targeted imaging and radioligands attack CAFs
- CSF1R, CD47/SIRPα, CXCR4, TGF-β, adenosine (A2A/CD73) agents target myeloid and stromal suppression; most have been modest so far
- Radiation and oncolytic viruses convert excluded tumours
Notes
top- Leading programmes: Tuveson (CSHL) on CAF subtypes; Sahai (Crick) and Mechta-Grigoriou (Institut Curie) on fibroblast heterogeneity; Joyce (Ludwig Lausanne) on TAMs; MD Anderson and MSK spatial atlases; Human Tumor Atlas Network (NCI).