Cold tumours: immune deserts and exclusion
Tumours come in three immune weathers: inflamed (T cells inside, checkpoint drugs work), excluded (T cells stuck at the edge), and desert (no T cells at all). Most common cancers are excluded or desert, and turning them 'hot' is the central problem of immunotherapy.
Deserts arise from low antigenicity (low TMB, MHC loss), failed priming (few BATF3+ cDC1, low CCL4 because of tumour-intrinsic WNT/β-catenin signalling; PTEN loss; MYC-driven CD47/PD-L1), and absent chemokines (CXCL9/10 silenced by EZH2 and DNMT1). Exclusion arises from stroma: TGF-β-activated CAFs and dense collagen (Mariathasan 2018), CXCL12 from FAP+ fibroblasts, abnormal VEGF-driven vessels lacking adhesion molecules, and myeloid barriers. Inflamed tumours still fail through PD-L1, exhaustion and Tregs. Converters: radiotherapy and chemotherapy (immunogenic death, STING), oncolytic viruses and in situ vaccines, STING agonists (systemic versions disappointed), anti-VEGF and TGF-β blockade (bintrafusp alfa failed), FAP/CXCR4 targeting, epigenetic priming to restore chemokines, and antigen-independent killers (engagers, CAR-T) that do not need a hot tumour. Gene signatures (T-cell inflamed GEP, TIS) and spatial pathology grade the weather.
In one picture
Three kinds of town: one where the police already patrol the streets (inflamed), one where they mill about outside a wall (excluded), and one with no police station at all (desert). Removing the officers' handcuffs (PD-1 blockade) only helps in the first; the second needs a gate, the third needs recruitment.
Diagram
top- Radiotherapy, immunogenic chemotherapy and TOP1 ADCs to seed antigen and STING signalling; oncolytic viruses (T-VEC, RP1) and in situ vaccination
- Anti-VEGF and PD-1×VEGF bispecifics open the vessel gate; FAP-, CXCR4- and TGF-β-directed agents (mostly modest so far)
- Epigenetic priming (EZH2, DNMT inhibitors) to restore chemokines; STING agonists intratumourally
- Bypass the weather: T-cell engagers, CAR-T, TCR-T and vaccines that bring or make their own T cells
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