Lung adenocarcinoma (ADC) harboring epidermal growth factor receptor (EGFR) mutations rarely transforms into squamous cell carcinoma (SCC) following resistance to targeted therapy. Here, we present a case of EGFR-positive ADC that transformed into EGFR-negative SCC after developing resistance to EGFR tyrosine kinase inhibitors (TKIs). The patient experienced progressive disease after one cycle of chemotherapy and subsequently underwent five courses of tislelizumab combined with chemotherapy. Although the primary tumor showed a partial response to this combined regimen, intracranial metastases continued to progress, ultimately leading to the patient's death. Notably, the patient survived for 8 months after SCC transformation with immuno-chemotherapy, a significantly longer duration than the previously reported median survival of 3.5 months. This case underscores the occurrence of genomic instability, histological transformation, and dissociated response (DR) following treatment with EGFR-TKIs in EGFR-positive lung ADC. We hypothesize that these phenomena may be driven by tumor heterogeneity and the dynamic variability within the tumor microenvironment (TME).