Abstract Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for non-small cell lung cancer (NSCLC), yet only a subset of patients achieves durable benefit due to primary and acquired resistance. We previously reported elevated kynurenine (KYN) in cisplatin-resistant NSCLC. KYN, produced by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), promotes immune evasion by diminishing CD8+ T-cell responses and expanding regulatory T cells (Tregs). Clinical failure of selective IDO1 inhibition in cancer suggests compensatory TDO2 upregulation as one of the resistance mechanisms. To target redundant KYN production, we evaluated the efficacy of a dual IDO1/TDO2 inhibitor (AT-0174; Antido Therapeutics) in preclinical models of cisplatin-resistant NSCLC. Efficacy and mechanism were assessed in vivo via a syngeneic orthotopic mouse model. Dual inhibition significantly reduced tumor volume (n=10, p0.01) and prolonged survival in the mouse model. These effects correlated with increased activity of CD8+ T cells and natural killer (NK) cells, as well as reduced frequencies of immunosuppressive Tregs and myeloid-derived suppressor cells (MDSCs). Combining AT-0174 with anti-PD-1 therapy produced a synergistic effect, further suppressing tumor growth and significantly improving survival in mice (log-rank, p=0.0001). We then developed a patient-derived organoid tumor (PDOT) platform that closely recapitulates the molecular and metabolic features of each patient's NSCLC. Single-cell RNA sequencing demonstrated ∼70% transcriptional similarity to original tumors, and metabolomic profiling confirmed comparable pathway activity. IDO1 protein was detected in all PDOTs. Co-culture with patient-matched PBMCs revealed that PDOTs with high baseline PD-L1 and kynurenine (KYN) expression were highly sensitive to dual IDO/TDO inhibition combined with pembrolizumab, resulting in increased immune cell infiltration (n = 10, p 0.005). This microfluidic PDOT system enables functional, patient-specific assessment of KYN pathway reliance, supporting timely stratification of NSCLC patients and rational design of combination regimens integrating metabolic targeting with immune checkpoint inhibitors. These findings provide a strong rationale for clinical evaluation of dual IDO/TDO inhibitors alongside checkpoint blockade. Citation Format: Manojavan Nagarajan, Chunjing Wu, Dao M. Nguyen, Estelamari Rodriguez, Emily Kim, Diane Lim, George Theodore, Irving Vidaurre, Wei Sha, Adeline Murphy, Jose Gomez, Durga Prasad Gannamedi Hinder, David Lombard, Lynn G. Feun, Niramol Savaraj, Medhi Wangpaichitr. Utilizing patient-derived organoid tumor models to combat chemo-immunotherapy resistance in NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4737.
Nagarajan et al. (Fri,) studied this question.