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Seven steps the immune system must complete to kill a tumour: release of antigens, pick-up by dendritic cells, priming of T cells in lymph nodes, travel, entry into the tumour, recognition, and killing. Every immunotherapy pushes on one step; every escape blocks one.
Chen and Mellman's cycle: (1) dying tumour cells release neoantigens; (2) dendritic cells (BATF3+ cDC1) capture and cross-present them; (3) in lymph nodes, T cells are primed via TCR-MHC plus CD28-B7, with CTLA-4 as the brake; (4) effector T cells traffic via CXCL9/10-CXCR3; (5) infiltrate through vasculature and stroma; (6) recognise peptide-MHC-I; (7) kill via perforin/granzyme and IFN-γ, releasing more antigen. Each step has failure modes (low antigenicity, poor DC function, Treg-dominated priming, abnormal vessels, TGF-β stroma, MHC loss, PD-1 exhaustion) and matching drugs (radiation, STING agonists and vaccines for 1-2; anti-CTLA-4 for 3; anti-VEGF for 4-5; engagers and CAR-T bypass 6; anti-PD-1 for 7).
A relay of seven runners. The race is only won if every baton is passed. Cancers usually drop only one or two batons, so the treatment that works is the one that fixes the step that actually failed, which is why the same drug cures one patient and does nothing for the next.
The first credible response signal in microsatellite stable colorectal cancer, and the reason the field's attention has moved to Fc engineering and to excluding patients with active liver metastases, in whom responses are rare.
For colon cancer that is mismatch-repair deficient (about 10-15% of colon cancers, more in older patients), a single short course of immunotherapy before surgery is now a reasonable standard and is far more effective than chemotherapy, which has little effect in this subtype. It requires testing every colon cancer for mismatch repair at diagnosis, before surgery. Whether some patients can safely skip surgery, as in dMMR rectal cancer, is the next question.
It is the positive half of the tumour mutational burden story and it applies only to single-agent immunotherapy, which is the setting fewest patients are treated in.
This is the result that ended tumour mutational burden as a practical selector in lung cancer: in the regimen most patients receive, it selects nobody, and neither do the co-mutations most often quoted as reasons to withhold immunotherapy.
It is the strongest case that mutation burden is real biology in lung cancer and, at the same time, the clearest demonstration that its threshold is not fixed, which is why it never became a reliable selector.
It offers the first credible explanation for why only a minority of small-cell patients get a durable benefit from checkpoint blockade, and it introduces subtype switching, which would mean retesting at relapse rather than typing once.
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 is the argument for sequencing every man with advanced prostate cancer rather than only the ones who look high risk: the phenotype is uncommon, it is invisible clinically, it opens the only durable immunotherapy route in this disease, and in one man in five it also identifies Lynch syndrome in the family.
Shares Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer, MSH2 loss in primary prostate cancer, Prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade, NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients and the tags mechanism, mechanics-atlas.
Shares Immunogenic cell death, CD3, PD-1 / PD-L1 immune checkpoint & T-cell activation, T-cell engagers (bispecific) and the tags mechanism, mechanics-atlas.
Shares IDO1, Hot vs cold tumours, VEGF / VEGFR, PD-1 and the tags mechanism, mechanics-atlas.
Shares Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer, Neoantigen, PD-1, Pembrolizumab and the tags mechanism, mechanics-atlas.
Shares VEGF angiogenesis, Ivonescimab, VEGF / VEGFR, PD-1 and the tags mechanism, mechanics-atlas.
Shares Theories of cancer: how the ideas connect, Cold tumours: immune deserts and exclusion, Hot vs cold tumours, PD-1 and the tags mechanism, mechanics-atlas.
Shares Cold tumours: immune deserts and exclusion, VEGF / VEGFR, PD-L1, Immune checkpoint inhibitors and the tags mechanism, mechanics-atlas.
Shares cGAS-STING innate sensing, SBRT / SABR (stereotactic radiotherapy), Non-small-cell lung cancer and the tags mechanism, mechanics-atlas.