Single-Cell and Spatial Transcriptomics Reveal CHCHD3 as a Therapeutic Target to Activate cGAS-STING and Overcome Immunosuppression in Lung Adenocarcinoma.

CHCHD3 promotes chemoimmunotherapy resistance in lung adenocarcinoma by inhibiting cGAS-STING signaling, with knockout restoring immune activation and tumor suppression.

• Why it matters: Overcoming intrinsic resistance to chemoimmunotherapy in lung adenocarcinoma is critical for improving patient outcomes, as many patients do not respond to current treatments. Understanding the mechanisms behind this resistance can lead to new therapeutic strategies.
• What they did: Using single-cell RNA sequencing and spatial transcriptomics on clinical samples, the study identified CHCHD3 upregulation in non-responders and demonstrated its role in sequestering cGAS in mitochondria, reducing immune activation. A small molecule, TN4510, was identified to disrupt this interaction.
• The result: Targeting CHCHD3 with TN4510 restored STING signaling, enhanced immune cell infiltration, and synergized with chemoimmunotherapy to inhibit tumor growth, providing a promising approach to overcome resistance in LUAD.