# Target-Centric Multiplexed Screening of an Herbal Extract Identifies a Novel Dual A2A/A2B Receptor Antagonist for Cancer Immunotherapy

## TL;DR

A new compound from a medicinal herb was found to block two receptors involved in cancer immunosuppression, potentially improving cancer treatments.

## Contribution

A novel dual antagonist for A2A and A2B receptors was identified from an herbal extract using a multiplexed screening platform.

## Key findings

- ER-15, a compound from a medicinal herb, acts as a dual antagonist for A2AR and A2BR.
- ER-15 reversed adenosine-mediated immunosuppression in animal models and tumor organoids.
- The compound showed potential to enhance immune checkpoint inhibitor therapy in anti-PD-1-resistant tumors.

## Abstract

Medicinal herbs contain natural products (NPs) possessing
rich
scaffolds valuable for drug discovery, particularly in oncology. While
most NP-derived cancer therapeutics directly kill tumor cells, emerging
opportunities lie in modulating antitumor immunity. However, target-annotated
NPs for cancer immunotherapy remain scarce. Herein we established
a multiplexed platform combining virtual screening, affinity selection-mass
spectrometry, and metabolomics profiling to identify bioactive NPs
targeting the adenosine 2A receptor (A2AR), a master regulator
of tumor immunosuppression. Screening the crude extract of a medicinal
herb and isolating the active constituent resulted in the discovery
of a novel dual antagonist for A2AR/A2BR with
preferential activity on A2AR. This compound, ER-15, adopts
a unique binding mode as revealed by structural modeling, MD simulations,
mutagenesis, and SAR analysis. Functionally, ER-15 reversed adenosine-mediated
immunosuppression and augmented the immune checkpoint inhibitor therapy
in both the animal model and patient-derived tumor organoids, supporting
its therapeutic potential in anti-PD-1-resistant tumors. Therefore,
our strategy is expected to overcome traditional NP discovery bottlenecks,
enabling efficient identification of target-annotated novel leads
for drug development.