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Despite significantly improving outcomes in non-small cell lung cancer (NSCLC), neoadjuvant chemoimmunotherapy (NCIT) fails to achieve a major pathological response (MPR) in over 40% of patients. Consequently, the early identification of non-responders prior to treatment initiation remains a critical unmet clinical need.

In this study, we performed single-cell RNA sequencing (scRNA-seq) on pre-treatment NSCLC tissue samples and integrated data from two public databases to identify signaling pathways associated with poor treatment response. Key findings were subsequently validated using multiplex immunofluorescence (mIF), and the predictive value of identified molecules was finally assessed in our cohort and GEO datasets.

Among the 83 patients, 23/57 (40.35%) of these radiological responders failed to achieve MPR. Data analysis revealed activation of stress-related signaling pathways in cancer-associated fibroblasts (CAFs) and T cells from nMPR patients, with elevated expression of stress-related markers, including BAG3 and IFITM2. MIF confirmed that BAG3⁺IFITM2⁺ CAFs and BAG3⁺CD8⁺ T cells were spatially adjacent and significantly more abundant in nMPR patients. In our cohort and the two public databases, the BAG3⁺ CAF-T Cell Neighborhood was significantly more abundant in the nMPR group compared to the MPR group (p<0.05). In the MPR group, there was no significant difference in BAG3⁺ CAF-T Cell Neighborhood between the radiological PR and non-PR subgroups. The AUC values of BAG3⁺IFITM2⁺ CAFs, BAG3⁺CD8⁺ T cells, and the BAG3⁺ CAF-T Cell Neighborhood were 0.84 [95%CI: 0.746-0.931], 0.72 [95%CI: 0.603-0.835], and 0.87 [95%CI: 0.787-0.948], respectively. The OS and DFS of the BAG3⁺ CAF-T Cell Neighborhood high group are significantly decreased than that of the low group (p<0.05). The level of BAG3⁺ CAF-T Cell Neighborhood outperformed other two indicators in predicting non-response to NCIT. Consistent results were observed in GSE126044 and GSE135222.

The BAG3⁺ CAF-T Cell Neighborhood may serve as a biomarker for predicting non-response to NCIT in NSCLC, with significant potential to inform clinical decision-making.