CD276 promotes immune evasion in clear cell renal cell carcinoma via NF-κB-IL-6-STAT3 signaling crosstalk
Year: 2026
Type: article
Abstract: Background: Clear cell renal cell carcinoma (ccRCC) exhibits prominent immune infiltration and inflammatory signaling, yet the tumor-intrinsic mechanisms that promote immune evasion remain incompletely defined. CD276/B7-H3 is linked to an unfavorable prognosis in ccRCC, but its involvement in regulating inflammatory immune suppression requires clarification. This study aimed to determine whether tumor-cell CD276 drives nuclear factor kappa B (NF-κB)-interleukin (IL)-6-signal transducer and activator of transcription 3 (STAT3) signaling and macrophage-dependent immune evasion in ccRCC.Methods: The Cancer Genome Atlas (TCGA)-Kidney Renal Clear Cell Carcinoma cohort (KIRC) data were analyzed to assess CD276 expression, prognosis, and immune-related signatures. Stable CD276-knockdown 786-O and Caki-1 cells were generated using shRNA. Cell proliferation, invasion, NF-κB activation, cytokine secretion, and STAT3 signaling were evaluated using Cell Counting Kit-8 (CCK-8), Transwell assays, Western blotting, immunofluorescence, luciferase reporter assays, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). Tumor-conditioned media were applied to THP-1-derived macrophages to examine STAT3-dependent polarization. Macrophage-T-cell co-culture assays were used to assess T-cell activation, cytokine secretion, and proliferation.Results: CD276 was highly expressed in ccRCC tissues and was associated with poorer overall survival (OS) and enrichment of macrophage-related and IL-6-JAK-STAT3 immune signatures. CD276 knockdown inhibited ccRCC cell proliferation and invasion, reduced NF-κB p65 nuclear translocation and transcriptional activity, and decreased IL-6 production. CD276 silencing also attenuated STAT3 phosphorylation in tumor cells and macrophages. Conditioned media from CD276-knockdown cells suppressed CD206⁺CD163⁺ macrophage polarization, decreased ARG1 and IL-10 expression, and increased iNOS expression. Functionally, macrophages exposed to CD276-deficient tumor media showed reduced suppression of CD3⁺ T-cell activation, interferon gamma (IFN-γ) and IL-2 secretion, and proliferation. Recombinant IL-6 restored, whereas STAT3 inhibition or IL-6 neutralization diminished, these effects.Conclusions: CD276 promotes ccRCC immune evasion by activating an NF-κB-IL-6-STAT3 signaling axis that drives immunosuppressive macrophage polarization and T-cell dysfunction.
Institution: First Affiliated Hospital of Soochow University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223947077