Background <p>We previously demonstrated that interleukin-33 (IL33) plays a key role in treatment resistance through tumor polyploidization and the consequent immune dysfunction by recruiting and expanding various immunosuppressive cells that express its receptor ST2, and that anti-IL33 blockade therapy induces potent anti-tumor effect in mouse tumor models resistant to anti-PD1 therapy. These suggest that IL33 and ST2 are potentially promising targets that could contribute to anti-PD1/PDL1 therapy. Recently, an increasing number of clinical studies have shown a significant correlation between IL33 expression in tumor tissues and poor prognosis in patients with gastric cancer (GC). However, the clinical significance of targeting the IL33-ST2 axis in anti-PD1/PDL1 therapy for GC remains unclear.</p> Methods <p>Tumor tissues and peripheral blood were collected from patients with advanced GC before and after nivolumab monotherapy in the WJOG10417GTR study. Gene expression of <i>il33</i> in tumor tissues, IL33 in plasma, and ST2⁺ cell subsets in four cell populations (IL17RB⁺GATA3⁺ ILC2s, CD117⁺FceRIa⁺ mast cells, CD11b⁺HLA-DR⁻PDL1⁺ MDSCs, and CD3⁺CD4⁺FOXP3⁺ Tregs) in peripheral blood cells were analyzed by RNA-sequencing, IHC, ELISA, or flow cytometry, and the relationship between their levels and patient prognosis was statistically analyzed.</p> Results <p>The levels of tumor <i>il33</i> gene expression and peripheral IL33 and ST2⁺ cells were higher in patients who showed progressive disease (PD) than in non-PD patients. High levels of tumor <i>il33</i> gene expression at post-treatment, and high levels of peripheral ST2⁺ cells at both pre- and post-treatment were significantly associated with shorter progression-free survival and overall survival. Patients with low post-treatment levels of both tumor <i>il33</i> and peripheral ST2⁺ cells, especially the mast cell subset, had long-term survival without PD, indicating durable responders.</p> Conclusions <p>These data suggest high IL33/ST2 levels are significant poor prognostic factors for nivolumab therapy for advanced GC. The IL33/ST2 axis may be useful as a biomarker for predicting and pre-selecting possible responders/nonresponders to anti-PD1/PDL1 therapy for GC, and hopefully as a druggable target for developing new drugs for treating GC. The IL33/ST2-targeting strategy will contribute to improving clinical outcomes in the treatment of GC.</p>