Targeting Adenosine, the Immune Brake of Hypoxic Tumors. Hero infographic showing the A2B receptor on a hypoxic tumor cell with adenosine accumulation and immune suppression. Below: the cascade Hypoxia to HIF-1a to CD39 and CD73 to Adenosine accumulation to A2A and A2B receptor activation to Immune suppression and Tumor growth.

The Setting

Why Mesothelioma First

A rare, aggressive cancer with a long-latency exposure history, no approved second-line therapy, and biology that lines up squarely with A2B blockade.

~3,000
New U.S. cases diagnosed annually
~94%
Global increase in cases, 1990 to 2021
400K+
9/11 responders, workers and residents exposed
~10%
5-year survival in pleural mesothelioma
~6 mo
Median survival after second-line therapy

The Mechanism

Mesothelioma: Built for A2B Blockade

In hypoxic mesothelioma tumors, adenosine accumulates to pathological levels that activate A2B-driven immune suppression and tumor growth. TT-4 is designed to block this pathway.

Mesothelioma: Built for A2B Blockade. Infographic showing the hypoxic mesothelioma tumor microenvironment with the cascade from hypoxia, HIF-1a, CD39 and CD73, to ATP being converted to adenosine at 100 to 500 times normal levels in the TME. The A2B receptor (A2BR) acts as the immune brake, driving T-cell suppression, Tregs and MDSCs, PD-L1 upregulation, tumor growth, and fibrosis and angiogenesis. TT-4 blocks this pathway, leading to immune reactivation, T-cell infiltration, tumor control, and checkpoint sensitization. Greater than 90 percent tumor-growth inhibition with TT-4 plus anti-PD-1 in mesothelioma model.

Our Lead Asset

TT-4: Purpose-Built for Selective A2B Blockade

An oral, once-daily small molecule engineered to block A2B in hypoxic tumors. Preclinical package exceeds IND requirements; GMP drug product manufactured and released.

Built For A2BR

Potent and selective by design

  • Single-digit nanomolar potency (Ki = 9.1 nM)
  • Best-in-class selectivity over A1, A2A and A3
  • Preclinical PK suggests prolonged A2B blockade
  • Efficacy across multiple preclinical cancer models

Built For Safety

Clean profile, predictable dosing

  • Greater than 3,000x selectivity over A1: mitigates CV and CNS risks
  • Clean toxicology, no drug-drug interaction signal
  • NOAEL greater than 11x proposed starting dose (200 mg)

Built For Scale

Practical for patients and payers

  • Low cost of goods
  • No cold-chain handling
  • Oral, once-daily dosing at home
  • Rapid manufacturing scale-up

Preclinical Evidence

TT-4 Outperformed Anti-PD-1 Alone

>90%
Tumor-growth inhibition with TT-4 + anti-PD-1 in mesothelioma model
p < 0.01
TT-4 monotherapy significantly outperformed anti-PD-1 alone

In an orthotopic AB1 mesothelioma model in immunocompetent BALB/c mice, TT-4 monotherapy reduced tumor burden more effectively than anti-PD-1 alone. Adding TT-4 to anti-PD-1 produced greater than 90% tumor-growth inhibition.

The mechanism is dual: direct anti-tumor activity, plus immune activation evidenced by increased T-cell infiltration and tertiary lymphoid structure formation in treated tumors.

Rosetti et al., AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics, 2025

Beyond Mesothelioma

A Modular A2B ± A2A Platform

Beyond mesothelioma, our investigational combination of TT-4 with TT-10, our A2A receptor antagonist, evaluates coordinated blockade of complementary adenosine receptor pathways.

TT-4 + TT-10

Coordinated A2B/A2A receptor blockade

Phase I/Ib evaluation in selected solid tumors where adenosine-driven immune suppression contributes to treatment resistance, including renal cell carcinoma, head and neck cancer, prostate cancer, and non-small cell lung cancer.

Explore Our Pipeline

See where TT-4 and the broader Cyncado portfolio sit in clinical development.

View PipelineMesothelioma Awareness