Pericytes Modulate Third‐Generation Tyrosine Kinase Inhibitor Sensitivity in EGFR‐Mutated Lung Cancer Cells Through IL32‐β5‐Integrin Paracrine Signaling

EGFR‐mutated lung cancer patients sometimes display restricted responses to third‐generation tyrosine kinase inhibitors (TKIs), potentially attributable to undervalued input from stromal cells, notably pericytes (PCs). The study shows that PCs isolated from EGFR‐mutated patients have a unique secretome profile, notably secreting IL32 and affecting signaling pathways and biological processes linked to TKI sensitivity. Clinical evidence, supported by single‐cell RNA sequencing and multiplex immunostaining of tumor tissues, confirms the presence of IL32‐expressing pericytes closely interacting with β5‐integrin‐expressing cancer cells in EGFR‐mutated patients, impacting therapeutic response and prognosis. Co‐culture and conditioned medium experiments demonstrate that PCs reduce TKI effectiveness in EGFR‐mutated cancer cells, a reversible phenomenon through silencing IL32 expression in PCs or depleting the IL32 receptor β5‐integrin on cancer cells, thereby restoring cancer cell sensitivity. Mechanistically, it is shown that YY1 signaling upregulates IL32 secretion in PCs, subsequently activating the β5‐integrin‐Src‐Akt pathway in EGFR‐mutated cancer cells, contributing to their TKI sensitivity. In animal studies, co‐injection of cancer cells with PCs compromises TKI effectiveness, independently of blood vessel functions, while inhibition of β5‐integrin restores tumor cell sensitivity. Overall, the findings highlight direct crosstalk between cancer cells and pericytes, impacting TKI sensitivity via IL32‐β5‐integrin paracrine signaling, proposing an enhanced therapeutic approach for EGFR‐mutated patients. This study investigates how pericytes regulate the sensitivity of EGFR‐mutated cancer cells to tyrosine kinase inhibitors (TKIs). It is found that YY1 transcriptionally upregulates IL‐32 secretion in pericytes, which binds to and activates β5‐integrin in cancer cells, triggering the Src‐Akt signaling pathway and reducing TKI sensitivity. Targeting pericytes’ paracrine effect could restore TKI sensitivity in lung cancer.