Mechanisms of immunotherapy resistance in small cell lung cancer

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a poor prognosis. Although the addition of immunotherapy to chemotherapy has modestly improved outcomes, most patients rapidly develop resistance. Resistance to immunotherapy can be broadly categorized into primary resistance and acquired resistance, as proposed by the Society for Immunotherapy of Cancer (SITC) consensus definition. Primary resistance occurs in the setting of failure to respond to immune checkpoint inhibitors (ICIs), while acquired resistance develops after initial response. The mechanisms of acquired and primary resistance to ICI are not well understood in SCLC, denoting an area of critical unmet need. Both intrinsic and extrinsic mechanisms play significant roles in immunotherapy resistance. Intrinsic mechanisms include defects in antigen presentation, mutations in key genes, reduced tumor immunogenicity, and epigenetic alterations. Extrinsic mechanisms involve the tumor microenvironment (TME), which is a complex interplay of both tumor- and immunosuppressive immune cells, vasculature, and microbiome. An understanding of these resistance mechanisms is crucial for developing novel therapeutic strategies to advance effective immunotherapy in patients with SCLC, a critical area of unmet need.