IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages - research summary

Sep 21, 2026

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Immunotherapy, especially PD-1 antibody treatment, has improved gastric cancer outcomes, yet a subset of patients shows poor response, requiring clearer resistance mechanisms. A retrospective analysis of 106 stage IV gastric cancer patients compared plasma cytokines between PD-1 resistant and sensitive groups and identified elevated IL-4 in resistant patients. IL-4 activates PI3K/AKT/mTOR signaling in macrophages, enhancing ATP production, glycolysis, and lactic acid production while upregulating FcγRIIB, ultimately impairing CD8+ T cell function and promoting PD-1 resistance.

LanguageEnglish

CategoryHealthcare

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Background

Immunotherapy in gastric cancer and PD-1 blockade

Study context and clinical evidence

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages Jiayu Zhang 1,2,3,5, Yu Dong 1,2,5, Shan Yu1,2,5, Keshu Hu 1,2,5, Lingyun Zhang 1,2,5, Min Xiong4, Mengling Liu1,2, Xun Sun1,2, Suyao Li1,2, Yitao Yuan1,2, Chi Zhang 1,2, Mengxuan Zhu1,2, Yichou Wei1,2, Yanjing Zhu1,2, Yiyi Yu1,2 ✉, Pengfei Zhang 1,2 ✉ and Tianshu Liu 1,2 ✉ © The Author(s) 2024 | | | | | --- | --- | --- | | | In recent years, immunotherapy, particularly PD-1 antibodies, have signiﬁcantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with ﬁrst-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identiﬁed elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These ﬁndings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | gastric cancer patients. | | | | | Cell Death and Disease (2024)15:500; [https://doi.org/10.1038/s41419-024-06875-4](https://doi.org/10.1038/s41419-024-06875-4) | | | | | | BACKGROUND According to the global cancer statistics in 2020, gastric cancer ranks ﬁfth in morbidity and fourth in mortality worldwide [1] . Due to the atypical symptoms of early gastric cancer and the insufﬁcient popularization of screening for gastric cancer, it is reported that one-third of patients have developed distant metastases at the time of initial diagnosis [2], which means that such patients cannot get radical surgery in the short term, and can only take systemic antitumor therapy. In recent years, immunotherapy represented by immune checkpoint inhibitors, especially PD-1 antibody, has effectively improved the prognosis of gastric cancer patients. Since the activation and killing effects of the immune system are suppressed in the tumor microenvironment, restoring the function of CD8+T cells through immunotherapy is currently the focus of research in the ﬁeld of gastric cancer. With the continuous development of tumor immunology research, PD-1, CTLA-4 and PD-L1 have all become relatively mature immunotherapy targets, among which PD-1 antibody is the most commonly used in the immunotherapy of gastric cancer. PD-1 is one of the known immune checkpoints, mainly expressed on the surface of activated T cells. PD-1 and its ligands PD-L1 (CD274) or PD-L2 (CD273) play a key role in the immune escape of tumor cells, which can signiﬁcantly inhibit the function of T cells, while tumors can resist the attack of the immune system through high expression of PD-L1/PD-L2 . By blocking the interaction between PD-1 and its ligand, immune system can normally recognize and kill tumors, so as to enhance the antitumor activity, which is the core of immunotherapy. Currently, multiple clinical studies have shown that immune checkpoints blocking treatment can effectively enhance antitumor activity and improve prognosis in gastric cancer patients. ORIENT-16 study conﬁrmed that ﬁrst-line immunotherapy comb

FAQs

What problem does the study address in gastric cancer immunotherapy?

Some gastric cancer patients do not respond well to PD-1 antibody–based immunotherapy. The study focuses on understanding resistance mechanisms and potential predictive markers.

How did the researchers identify a factor associated with PD-1 resistance?

They retrospectively compared plasma cytokine levels between PD-1 resistant and sensitive stage IV gastric cancer patients and found elevated IL-4 expression in resistant cases.

What mechanism links IL-4 to immunotherapy resistance?

IL-4 induces metabolic and signaling changes in macrophages through the PI3K/AKT/mTOR pathway, increases ATP and glycolysis-related activity, upregulates FcγRIIB, and leads to CD8+ T cell dysfunction, driving PD-1 resistance.

Sep 21, 2026

Upload by Liam