Bitter Taste Receptors (TAS2R): New Targets for Treating Asthma, Preterm Birth, and Cancer

Bitter taste receptors are not just about the tongue and “ugh, not tasty.” It turns out that these sensors (TAS2R family) are located throughout the body — from the intestines and respiratory tract to the smooth muscles of blood vessels — and participate in the regulation of immune responses, metabolism, and even cell division. That is why today they are seriously considered as new targets for the treatment of neurodegenerative diseases, asthma, oncology, and more. This is the conclusion of a large review in the journal Theranostics.

Why is this important?

The same molecular “danger sensor” is embedded in key barrier organs. This means it can be manipulated pharmacologically – both by direct TAS2R agonists and by “smart” drug carriers targeting these receptors. This approach simultaneously opens up new anti-inflammatory, bronchodilator, tocolytic, and antitumor strategies – with a chance of being targeted and with low systemic toxicity.

What are these receptors and where to look for them?

TAS2R are receptors of the GPCR class (seven transmembrane helices); about 25 genes of this family have been described in humans. Some of them are “polygamous” and recognize dozens of bitter molecules, others are very selective. And, most importantly, they are expressed far beyond the taste buds: in the intestinal epithelium, respiratory tract, gums, etc.

The mucous membranes contain special chemosensitive cells (SCCs) and “tuft cells” that carry taste signaling proteins: they recognize allergens and microbes, trigger the innate immune response, and help regulate the microbiome and type II immune response in the gut. In simple terms, these are “dirt and threat” sensors embedded in the body’s barriers.

What was already known?

• In the airways, TAS2R activation on smooth muscle results in rapid Ca²⁺ signaling, opening of K⁺ channels and bronchial relaxation, and on ciliated epithelium, increased ciliary clearance and antimicrobial effects.
• In the intestinal and respiratory mucosa, tuft cells/chemosensory cells that use taste signaling trigger the innate immune response and regulate interactions with the microbiota.
• In uterine smooth muscle, activation of individual TAS2R blocks Ca²⁺ entry and inhibits contractions.
• In a number of tumors, high expression of certain TAS2Rs is associated with improved survival, and their stimulation in cell/animal models triggers apoptosis and reduces migration, invasion, stemness (CSC traits) and drug resistance.
• Polymorphisms (eg, TAS2R38) are associated with variability in upper respiratory tract innate immunity and susceptibility to infections, hinting at personalization.

What remained unclear?

The picture was still fragmented: different TAS2R subtypes, different tissues and models showed heterogeneous effects. What was needed was a review that:

1. will link mechanisms (common signaling cascades, cross-talk with MAPK/ERK, Akt, mitochondrial apoptotic pathways, NO/cGMP),
2. compare tissue-specific functions (bronchospasm, tocolysis, immunomodulation, barrier effects),
3. will bring together in one place preclinical therapeutic areas (asthma/COPD, premature birth, oncology, neurodegeneration) and targeted delivery technologies (nano targeting of TAS2R subtypes).

Why does the clinic need this: several directions

Neurodegeneration. In the CNS, chronic inflammation and oxidative stress fuel neuronal death in Alzheimer's and Parkinson's disease. The review suggests that TAS2R activation may interfere with these signaling pathways; strategies for targeted drug delivery "via" TAS2R are also considered. This is still a research agenda, but it is gaining momentum.

Premature birth. A very unusual line: switching on bitter receptors in the myometrium (uterine muscle) sharply relaxes the already contracted uterus, blocking calcium signals - in experiments on mice, the effect was stronger than that of current tocolytics. The idea is to create a new class of drugs for the prevention of premature birth, targeting TAS2R.

Oncology.

• In head and neck squamous cell carcinoma, bitter agonists via TAS2R increase intracellular calcium, leading to mitochondrial depolarization, caspase activation, and apoptosis. Higher TAS2R expression was correlated with better survival—a potential prognostic marker and therapeutic target.
• In pancreatic adenocarcinoma, TAS2R10 “sweetens the pill” of chemotherapy: caffeine (its ligand) increased the sensitivity of cells to gemcitabine and 5-FU; mechanistically, through the suppression of Akt phosphorylation and expression of the ABCG2 drug resistance pump. There is also a prototype of targeted delivery: a liposome targeting TAS2R9 more precisely accumulated in the tumor and inhibited its growth in mice.
• In neuroblastoma, TAS2R8/10 overexpression reduced stemness (CSC features), migration and invasion, and downregulated HIF-1α and its metastatic targets.
• In acute myeloid leukemia, TAS2R activation inhibited proliferation (G0/G1 arrest), turned on caspases, and reduced migration—further clues for drug strategies.
• In breast cancer, TAS2R4/14 stimulation suppressed migration and proliferation via MAPK/ERK and G protein cascades, candidate low-toxicity targets.

Why is this promising?

The idea is simple: since TAS2Rs “know how” to regulate inflammation, metabolism, smooth muscle tone, and cell survival programs, they can be controlled by bitter ligands or drug carriers that target specific receptor subtypes. This opens the way to anti-inflammatory/bronchodilatory strategies, antitumor strategies, and targeted delivery.

Cautious optimism

Most of the data are from cellular and preclinical models; clinical trials are still few and far between. But the breadth of TAS2R's "location" and functions makes it a rare example of a sensory system that could become a fully-fledged pharmacological tool, from obstetrics to oncology. It's worth keeping an eye on.