KEAP1 mutation

Collectively, we associated the redox status mediated by loss-function mutations of KEAP1 or STK11 to immune evasion and immunotherapeutic resistance by suppressing STING/MDA5 expression and interferon signaling of cancer cells. Our findings link redox homeostasis to STING/MDA5 expression and tumor immunogenicity, raising the possibility that targeting this axis could represent a future strategy to enhance ICI efficacy.

Moreover, SMARCA4 deficiency leads to poor responses to immunotherapy, potentially due to core metabolic disorders, inactivation of tumor suppressor signaling, and immune suppression in the tumor microenvironment. These findings suggest that treatment strategies should be adjusted to address these molecular mechanisms.

Notably, MAP2K1 E102-I103 deletion was frequently observed in pre-invasive samples, which endowed alveolar type II cells with increased growth potential and initiated tumor formation, suggesting that it is a potential driver mutation of LUAD. In summary, our study highlights key molecular changes during the stepwise progression of LUAD, provides insights into the identification of novel therapeutic targets, and helps to define the curative time window for this disease.

Furthermore, in vivo studies using KRAS-mutant H358 xenograft models confirm the potent anti-tumor effects of EB. Collectively, our findings establish that EB triggers ferroptosis in KRAS-mutant NSCLC by activating the Keap1-Nrf2/HO-1 pathway, suggesting a promising therapeutic strategy for this challenging malignancy.

In KRAS-mut NSCLCs with or without STK11/KEAP1 mutations, the GPAs in the DNA-binding genes ARID1A/ARID2 affected the outcomes of immunotherapy, possibly through the downregulation of STING expression.

Emerging evidence supports rational combination strategies, including parallel inhibition of epidermal growth factor receptor, protein tyrosine phosphatase non-receptor type 11 or SOS1 and vertical blockade of the mitogen-activated protein kinase-extracellular signal-regulated kinase or phosphatidylinositol 3-kinase-mechanistic target of rapamycin cascades; immunotherapies such as checkpoint blockade, T-cell receptor (TCR)-T cells, bispecific T-cell engagers or cytokine-armed oncolytic viruses; metabolic interventions targeting macropinocytosis or autophagy; as well as radiotherapy...Precision approaches that integrate multiomics profiling with longitudinal circulating tumour DNA analysis enable biomarker-guided patient selection (eg, based on STK11 and KEAP1 comutations) and support therapeutic adaptations, including sequencing strategies and intermittent dosing. Thus, network-level KRAS interception combined with biomarker-driven, clonal evolution-informed trial design offers a path towards sustained control of KRAS-driven cancers.

These findings suggest that UXS1 loss is synthetic lethal with NRF2 activation and may be a promising target for therapy. See related article by Gebru et al., p. 4806.

P1, N=22, Active, not recruiting, National Cancer Institute (NCI) | N=85 --> 22 | Trial completion date: Jun 2026 --> Nov 2026 | Trial primary completion date: Jun 2026 --> Nov 2025

In PD-L1 TPS ≥ 50% NSCLC patients treated with pembrolizumab, our results suggest an improved PFS in patients predicted to be KEAP1/NFE2L2 mutated.

The chymotrypsin of fish fed the A25T10 diet was significantly higher than those in other groups (p < 0.05)...In this study, taurine supplementation can down-regulate the expression of intestinal pro-inflammatory factors (interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8)) and up-regulate the expression of anti-inflammatory factor interleukin-10 (IL-10), enhance intestinal immunity, and improve intestinal digestion and absorption. Therefore, the addition of 1-1.5% taurine to low-fishmeal feeds can improve the growth performance of golden pompano.

Further research is therefore essential to define biomarkers of Nrf2 dependency, optimize therapeutic windows, and integrate pathway modulation into precision medicine frameworks. A deeper understanding of this regulatory axis may ultimately transform Nrf2 from a compelling molecular target into a cornerstone of redox-based precision therapeutics.

P1, N=41, Terminated, Novartis Pharmaceuticals | N=140 --> 41 | Trial completion date: Jul 2027 --> Oct 2025 | Recruiting --> Terminated | Trial primary completion date: Jul 2027 --> Oct 2025; The trial was terminated due to a business decision and not as a result of any safety concerns