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T cells that see their target for weeks on end without winning gradually shut down: they raise a set of brakes (PD-1, LAG-3, TIM-3, TIGIT), lose their ability to kill, and eventually lock this state into their DNA. Checkpoint drugs rescue the ones that are only partly exhausted; the terminally exhausted are beyond reach.
Chronic TCR stimulation with insufficient help drives a stepwise programme: TCF1+ progenitor-exhausted cells (stem-like, lymph-node and tertiary-lymphoid-structure resident, PD-1 intermediate) self-renew and give rise to transitory effector-like cells and then terminally exhausted cells (PD-1 high, TIM-3, CD39, CD101) with poor IL-2/TNF/IFN-γ production, driven by NFAT without AP-1, TOX and NR4A, and fixed by DNMT3A-dependent de novo methylation ('epigenetic scarring'). PD-1 blockade expands the progenitor pool and its transitory progeny rather than reviving terminal cells; response correlates with the size of the TCF1+ reservoir and with CD28 co-stimulation (PD-1 dephosphorylates CD28). Co-inhibitory receptors partition: LAG-3 (MHC-II, FGL1) blocked by relatlimab; TIGIT (CD155) by tiragolumab (mixed phase 3 results); TIM-3 (galectin-9, CEACAM1) by sabatolimab. CAR-T cells exhaust the same way (CD8 CAR-T with c-Jun overexpression or TET2 loss resist it); interval rests and PD-1 knockout are engineering countermeasures.
A soldier posted at a wall for months with no relief. First tired, then unwilling to fire, finally unable to, and the last stage is written into their habits so deeply that no order can undo it. Checkpoint inhibitors work on the tired, not the broken.
It corrected a widely repeated simplification. An STK11 or KEAP1 mutation is not by itself a reason to expect immunotherapy to fail; it is a reason to expect it in a KRAS-mutant tumour, which is how the result should be read on a report.
It turned a frequently reported variant into an interpretable one: the class decides whether the stain will be negative, how poor the prognosis is, and whether immunotherapy is more rather than less likely to help.
It separated the prognostic co-mutation, KEAP1, from the predictive one, STK11, in a disease where the two are often quoted together, and it is the reason KEAP1 status is worth reading off a report even though no treatment depends on it.
One of the most cited trial reports Europe PMC returns for KRAS in Non-small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
It is the origin of the idea, now central to lung oncology, that the co-mutation and not the driver decides how a KRAS-mutant tumour behaves and whether immunotherapy will work.
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.
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