ILC2-derived IL-9 promotes eosinophil-mediated antitumor activity.

Innate lymphoid cells (ILCs) do not express diverse antigen receptors and widely reside in tissues, where they participate in barrier immunity, tissue inflammation, and maintenance of metabolic homeostasis by secreting cytokines ^[1]. Among them, the role of group 2 ILCs (ILC2s) in tumors has attracted increasing attention in recent years: studies have shown that ILC2s can infiltrate pancreatic ductal adenocarcinoma and amplify the efficacy of anti-PD-1 therapy ^[3]; in melanoma, they coordinate eosinophil recruitment and activation through GM-CSF secretion, and a high degree of ILC2 infiltration is associated with favorable prognosis ^[4]; IL-33-activated ILC2s can also induce tertiary lymphoid structures ^[6], and human ILC2s themselves can directly lyse tumor cells via granzyme B ^[7]. Meanwhile, the antitumor mechanisms of GITR costimulation have previously been described mainly in adaptive immunity—the GITR agonistic antibody DTA-1 depends on IL-9 to promote Th9 cell differentiation and enhance CTL responses ^[2]—whereas eosinophils have been shown to mediate tumor rejection by normalizing tumor vasculature in the presence of CD8+ T cells ^[5], and to enhance the efficacy of immune checkpoint blockade in breast cancer through cooperation with CD4+ T cell-derived IL-5 ^[8]. However, how GITR signaling functions in ILC2s, an innate lymphocyte population, and whether IL-9 can mediate antitumor effects through innate pathways independently of the adaptive immune system were previously unclear.

This new study combined analyses of human sequencing datasets with gene knockout mouse models and adoptive transfer experiments, finding that activation of GITR on tumor-infiltrating ILC2s induces the transcription factor ATF3 and drives abundant IL-9 production, far exceeding the concomitantly mildly upregulated IL-5 and IL-13. Mechanistically, ILC2-derived IL-9 enhances eosinophil survival, tissue retention, and cytotoxicity through tumor-induced IL-9 receptor expression, thereby promoting intratumoral eosinophil accumulation. Key functional evidence came from the findings that eosinophil depletion abolished GITR-mediated tumor control, whereas adoptive transfer of eosinophils restored this control. More importantly, this IL-9–eosinophil pathway could still suppress tumor growth in the absence of adaptive lymphocytes. In human datasets, IL-9 and eosinophil signature signals were associated with favorable prognosis in melanoma and lung adenocarcinoma.

Relative to prior knowledge, this work extends the antitumor mechanism of GITR agonists, previously thought to rely mainly on Th9–CTL adaptive immunity ^[2], to an axis mediated entirely by innate immune cells: ILC2s serve as the main source of IL-9, with eosinophils as the effector cells executing tumor-killing functions. Compared with the report that ILC2s recruit eosinophils via GM-CSF in melanoma ^[4], this study identifies IL-9 as the molecule linking the two cell types and defines its roles at three levels—eosinophil survival, retention, and cytotoxicity; it also indicates that GITR is the upstream switch activating this axis, providing a new cellular mechanistic basis for GITR agonist therapy.

Of course, these conclusions mainly derive from mouse models and correlative analyses of human datasets, and the association of IL-9 and eosinophil signatures with prognosis does not equate to causality; whether GITR agonism can reliably activate human ILC2s to produce IL-9 in patients, and how this innate pathway cooperates with known adaptive mechanisms ^[2] in therapeutic settings, still await clinical validation. In addition, ILC2s may also promote tumors in certain tumor contexts ^[3], and the net effect of GITR targeting across different tumor types remains to be clarified.