Non-small cell lung cancer (NSCLC) constitutes 80-85% of lung cancer cases and is a leading cause of cancer-related mortality. Most patients are diagnosed at metastatic stages, where curative treatment is rarely an option and the primary goal is to prolong survival while maintaining quality of life. Since NSCLC is often diagnosed in elderly individuals, comorbidities must also be considered in the treatment planning. Immune evasion is a central hallmark of cancer. By interactions between immune checkpoint molecules, such as programmed death 1 (PD-1) and its ligand PD-L1, as well as cytotoxic T-lymphocyte antigen 4 (CTLA-4), tumors downregulate immune responses, promoting self-tolerance and evading detection. Immune checkpoint inhibitors (ICIs) enhance the autoimmune function against cancer cells by blocking these targets and have wide evidence of efficacy in NSCLC. Currently, ICIs combined with chemotherapy are the standard of care for metastatic NSCLC without actionable mutations. In tumors with high PD-L1 expression, ICI monotherapy is also an effective option. In some cases, treatment associated toxicities and co-existing morbidities remain a challenge. In the case of patients with autoimmune disorders, they may experience exacerbation of the underlying autoimmune disease following ICI initiation and also an increased risk of immune-related adverse effects (irAE). People with underlying multiple sclerosis (MS) have mostly been excluded from clinical trials of ICIs, so data on their safety in the setting of MS is limited. This report presents three clinical cases from our institution involving patients with NSCLC and pre-existing MS who were treated with ICIs.