# Targeting FAM83D triggers tumor cell senescence via cGAS-STING signaling activation and reprograms TAMs to combat glioma

## TL;DR

This study shows that targeting FAM83D in glioma cells can trigger tumor cell senescence and reprogram tumor-associated macrophages, offering a new therapeutic strategy for glioma treatment.

## Contribution

The study introduces PSAG and reveals FAM83D as a novel target linking tumor cell senescence with macrophage reprogramming in glioma.

## Key findings

- Knockdown of FAM83D activates cGAS-STING signaling, inducing tumor cell senescence and suppressing glioma progression.
- FAM83D knockdown promotes M1 macrophage polarization through SASP and ANXA1-FPR1/2 signaling.
- The FAM83D-cGAS/STING-SASP-TAMs axis is critical for regulating the tumor microenvironment in glioma.

## Abstract

Glioma, a prevalent and aggressive primary brain tumor, has a poor prognosis despite the administration of standard treatment. Cellular senescence is thought to have a good protective effect in limiting the malignant progression of tumors, while the senescence-associated secretory phenotype produced by senescent cells may influence the activity of immune cells in the microenvironment. Macrophages, as a major component of the glioma microenvironment, play an important role in regulating the innate and adaptive immune responses which is essential for tumor suppression. Therefore, identifying potential targets that connect tumor cell senescence with macrophage reprogramming may facilitate the development of new therapeutic agents in glioma.

Here, we developed the CellToAge algorithm and leveraged high-throughput sequencing data to map senescence-associated signatures in glioma. Based on in vitro and in vivo experiments including the cell co-culture model, in situ allograft mouse model, and single-cell transcriptome sequencing, we further elucidated the interplay between tumor cell senescence and macrophage polarization induced by knockdown of FAM83D in glioma.

Notably, we identified the projected senescence-associated signatures in glioma (PSAG) and focused on the potential target FAM83D. In vitro and in vivo assays showed that knockdown of FAM83D resulted in abnormal cell division, which increased double-stranded DNA in the cytoplasm, thereby inducing tumor cell senescence by activating the cGAS-STING signaling to suppress glioma progression. Synchronously, knockdown of FAM83D could also induce glioma cells to produce a specific senescence-associated secretory phenotype (SASP), which promoted the senescence of neighboring tumor cells and drove macrophage polarization toward an M1 state. Additionally, ANXA1-FPR1/2 ligand-receptor signaling involved in tumor cells-macrophages crosstalk was associated with macrophage polarizations, which was further validated based on our clinical glioma cohort.

Our data revealed the critical role of FAM83D in regulating tumor cell senescence and shaping the tumor microenvironment with a specific impact on macrophage polarization. These insights open avenues for targeted therapeutic strategies aimed at modulating the FAM83D-cGAS/STING-SASP-TAMs axis in the management of glioma.

The online version contains supplementary material available at 10.1186/s13046-026-03681-y.