The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with epidermal growth factor (EGFR) receptor tyrosine kinase inhibitors (TKIs) is a relatively common phenomenon. However, transformation of non-small cell lung cancer (NSCLC) to SCLC following treatment with immunotherapy is very rare. Here, we report a case of a 56-year-old patient diagnosed with driver gene mutation-negative lung squamous cell carcinoma (SCC). He received four cycles of immunotherapy with sugemalimab and chemotherapy with albumin paclitaxel in combination with carboplatin, and a partial response was achieved. Subsequently, the patient received 5 cycles of immunotherapy with sugemalimab. However, he developed rapid progression of mediastinal lymph nodes, and biopsy results showed transformation to SCLC. His tumor did not respond to the next line of carboplatin combined with etoposide, and he died six months after the discovery of SCLC transformation. In conclusion, SCLC transformation is also an important resistance mechanism for lung SCC patients treated with immunotherapy and predicts a very poor outcome. Repeat biopsy is needed for advanced lung SCC that has progressed with immunotherapy.