{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:08:01Z","timestamp":1789427281747,"version":"build-2803163510"},"reference-count":152,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Tumor immune escape is increasingly recognized as an immunometabolic process shaped not only by immune checkpoints and suppressive cell populations, but also by nutrient competition and metabolic signaling within the tumor microenvironment. This nutrient-competitive environment is not limited to tryptophan depletion, but also involves glucose restriction, glutamine dependence, arginine metabolism, amino acid transporter competition, and impaired mitochondrial fitness of effector T cells. Among amino acid pathways, tryptophan metabolism has emerged as a central regulator of tumor\u2013immune interactions. Through the activity of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), kynurenine-producing branches, and both AHR-dependent and AHR-independent downstream programs, tumors establish a metabolic state that couples tryptophan depletion, metabolite signaling, redox adaptation, and immune suppression. Recent evidence further shows that tryptophan metabolism is not restricted to tumor cells, but also involves cancer-associated fibroblasts, macrophages, and T cells, thereby shaping multicellular crosstalk within immunosuppressive niches. Beyond immune suppression, this pathway contributes to ferroptosis resistance, stemness, metastatic adaptation, and resistance to chemotherapy, targeted therapy, and immune checkpoint blockade. In parallel, circulating metabolites and tissue-level metabolic profiling are being explored as potential biomarkers for patient stratification and treatment response prediction. In this review, we summarize the molecular basis of tryptophan catabolism in cancer, discuss its role in tumor\u2013immune\u2013stromal communication, and highlight emerging translational and therapeutic opportunities. Rather than reviewing tryptophan metabolism as a linear IDO1\/TDO2-centered pathway, we define it as a multicellular immunometabolic communication network in which tumor cells, stromal fibroblasts, myeloid cells, and lymphocytes exchange metabolic and signaling cues to create spatially organized immunosuppressive niches. This network-based view helps explain why single-enzyme inhibition is often insufficient and supports the development of biomarker-guided, multi-branch, and cell-context-specific therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1878140","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:57:12Z","timestamp":1783490232000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingyun","family":"Chen","sequence":"first","affiliation":[{"name":"Cancer Institute, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiheng","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Cancer Institute, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head & Neck, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27782","article-title":"Cd8(+) 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