Small‐cell lung cancer (SCLC) is characterized by its high malignancy and is associated with a poor prognosis. In the early stages of the disease, platinum‐based chemotherapy is the recommended first‐line treatment and has demonstrated efficacy. However, SCLC is prone to recurrence and is generally resistant to chemotherapy in its later stages.

Here, we collected samples from SCLC patients who received platinum‐based chemotherapy, performed genomic and transcriptomic analyses, and validated our results with publicly available data.

SCLC patients with DNA polymerase binding pathway mutations had an improved prognosis after platinum chemotherapy compared with patients without such mutations. Patients in the mutant (MT) group had higher infiltration of T cells, B cells, and M1 macrophages compared with patients without DNA polymerase binding pathway mutations.

DNA polymerase binding pathway mutations can be used as prognostic markers for platinum‐based chemotherapy in SCLC.