Targeting the ISR with small-molecule inhibitors (PERK or GCN2 inhibitors, ISRIB) or repurposed agents (metformin) demonstrates compelling preclinical efficacy in reversing immunosuppression and synergizing with immune checkpoint inhibitors. Biomarker-driven strategies, including ISR gene signatures and p-eIF2α immunohistochemistry, offer promising avenues for patient stratification. Thus, pharmacological targeting of the ISR represents a strategically viable approach to reprogram the immunosuppressive TME and overcome immunotherapy resistance in breast cancer, warranting urgent clinical investigation.

This analysis shows growing interest in repurposing metformin as a potential disease-modifying therapy for CNS disorders, with a focus on neurorepair and biomarker-based assessment. Larger, well-designed randomised controlled trials are still needed to confirm efficacy in humans.

PRS was used to optimize GACC-metformin-regorafenib combinations...In zebrafish xenografts, GACC (50 µM) reduced Hep3B tumor fluorescence by ~90% without detectable hepatotoxicity, whereas sorafenib decreased liver size/fluorescence...PRS identified an off-grid triple combination that reduced PLC/PRF/5 viability to 19% while maintaining THLE-2 viability at 52% and preserving zebrafish development. GACC is a G4-active cobalt-glutamate scaffold with anti-HCC activity and favorable zebrafish safety, and a zebrafish-plus-PRS workflow enables rational, less toxic combination design.

Clinical data further showed that high AMPK activity and increased γδ T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in γδ T cell-based immunotherapy for TNBC.

In 3T3-L1 adipocytes, all five compounds significantly enhanced insulin-stimulated glucose uptake at 10 μM, achieving efficacy comparable to that of metformin. In MIN6 cells, xanthohumol and cirsilineol increased glucose-stimulated insulin secretion to levels comparable to exendin-4, while curcumin, hesperetin, and (-)-epicatechin produced modest but significant increases. In conclusion, this integrated computational and experimental framework identified food-derived natural compounds with validated dual-pathway therapeutic activity against T2DM, providing a systematic and reproducible methodology for multi-target drug discovery in complex metabolic disorders.

P2, N=303, Recruiting, Karolinska Institutet | Not yet recruiting --> Recruiting

Because this pathway is readily inhibited by common nonsteroidal anti-inflammatory drugs (NSAID), the findings support clinical evaluation of combined metformin and NSAID therapy to improve HNSCC chemoprevention. See related article by Hoang et al., p. 79 .

In vivo, the system prolonged the circulation half-life to nearly 6 hours, effectively suppressed tumor growth, and demonstrated excellent biocompatibility with no significant toxicity or body weight loss. In conclusion, mem(DTX&Met@MSNs) integrates homologous targeting with dual-drug synergism, offering a safe and effective strategy for the treatment of HER2-positive breast cancer.

Herein, we design a lipid nano delivery system (MC@L) and exploit endothelial transcytosis to deliver metformin (Met) and CaO2 into tumor vascular endothelial cells (ECs) and tumor cells for achieving tumor vascular normalization-boosted antitumor immunotherapies...Additionally, MC@L internalized by tumor cells could cause CaO2-induced immunogenic cell death (ICD), together with hypoxia relief and acid neutralization mediated by O2 generation and H+ consumption during CaO2 degradation, thus further improving the immune effector cell functions under the accompaniment of Met-mediated inhibition of tryptophane uptake in tumor cells. Such a lipid nano delivery system greatly increases the susceptibility of 4T1 tumor-bearing mice to PD-L1 blockade efficacy.

P3, N=1174, Recruiting, The University of Queensland | Trial completion date: May 2027 --> Dec 2030 | Trial primary completion date: Dec 2026 --> Dec 2030

P2, N=72, Recruiting, University of Utah | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Dec 2025 --> Mar 2027

P1/2, N=25, Recruiting, Universita Degli Studi Di Milano Bicocca | Not yet recruiting --> Recruiting