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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.
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.
The clearest statement of why the corpus records so many negative immunotherapy trials here, and of the design logic behind the vaccine and agonist combinations now in trials.
It links the Lehmann subtypes to the spatial immune classes of Gruosso and gives a rationale for pairing checkpoint inhibitors with the immunomodulatory subtype and stromal or metabolic agents with the cold ones.
It is the definitive negative result for unselected checkpoint blockade in microsatellite-stable colorectal cancer, and the reason later attempts have moved to Fc-enhanced CTLA-4 antibodies, TGF-beta blockade and vaccines rather than PD-L1 plus MEK.
It explains why a PD-L1 score alone predicts imperfectly: PD-L1 on stromal cells with excluded T cells is a poor-outcome pattern, and B7-H4 marks the cold tumours now being targeted by antibody-drug conjugates.
It gives a genetic account of both immunotherapy failures: why some mismatch repair deficient tumours resist, and why the microsatellite-stable majority has no T cells in it to begin with.
It is the clearest mechanistic answer to why microsatellite-stable colorectal cancer resists immunotherapy, and the rationale for every TGF-beta plus checkpoint combination now in trials in this disease.
Two pathway pages and one bottleneck page on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Shares IDO1, CSF1R, Myeloid suppression: TAMs, MDSCs & don't-eat-me signals, Tumour microenvironment (TME) and the tags mechanism, mechanics-atlas.
Shares Immune surveillance and cancer immunoediting, Tumour-infiltrating lymphocytes (TILs), The cancer-immunity cycle, Hot vs cold tumours and the tags mechanism, mechanics-atlas.
Shares CSF1R, Myeloid suppression: TAMs, MDSCs & don't-eat-me signals, Tumour microenvironment (TME), Ivonescimab and the tags mechanism, mechanics-atlas.
Shares Desmoplasia (tumour stroma), FAP, TGF-β signalling, Fibroblast activation, desmoplasia & matrix stiffness and the tags mechanism, mechanics-atlas.
Shares CXCR4, CSF1R, Single-cell & spatial profiling, VEGF / VEGFR and the tags mechanism, mechanics-atlas.
Shares CSF1R, Myeloid suppression: TAMs, MDSCs & don't-eat-me signals, PD-1, Immune checkpoint inhibitors and the tags mechanism, mechanics-atlas.
Shares CXCR4, TGF-β signalling, SBRT / SABR (stereotactic radiotherapy), Colorectal cancer and the tags mechanism, mechanics-atlas.
Shares Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma, Tumour mutational burden (TMB), PD-L1, PD-1 and the tags mechanism, mechanics-atlas.