Small Molecule Activators of Antitumor Immunity.

Authors

Vaibhav Pal Singh, Motonari Uesugi

Published in

Accounts of chemical research. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

ConspectusImmune checkpoint blockade therapies have revolutionized cancer treatment. However, their clinical efficacy remains limited by dysfunctional T-cell states within the tumor microenvironment. These limitations are particularly evident in aged hosts, where metabolic and signaling impairments compromise immune fitness and reduce responsiveness to PD-1/PD-L1-directed therapies. Emerging evidence suggests that chemical modulation of immune cell function represents a promising strategy to overcome these barriers. Our work explores how small molecules can be leveraged to restore T-cell activity and potentiate antitumor immunity through complementary chemical mechanisms. By integrating cell-based screening with electrophile-focused chemoproteomics, we identified a covalent small-molecule activator, arvenin I, which engages a ligandable cysteine in MKK3, promoting signaling programs that revive exhausted T-cells and synergize with immune checkpoint blockade. In parallel, previous studies revealed that age-associated depletion of the endogenous polyamine spermidine contributes to impaired T-cell metabolism and diminished responses to checkpoint blockade. Using chemoproteomic tools, we profiled spermidine-interacting proteins and found that the majority were mitochondrial proteins, including lipid-metabolism factors. This chemoproteomic platform also enabled the identification of a biostable spermidine mimetic that restores mitochondrial fitness and enhances antitumor immune responses in vivo. Together, these studies establish a unified chemical biology framework in which covalent signaling activation and metabolite-inspired energy support converge to restore T-cell fitness. This Account highlights how chemoproteomic discovery can guide the development of immune-activating small molecules and underscores the potential of chemical approaches to complement and extend the impact of cancer immunotherapy.

PMID:
42342561
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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