Sex-based heterogeneity in non-small cell lung cancer (NSCLC) and response to immune checkpoint inhibitors (ICIs): a narrative review

Objective: The aim of our review is to analyse sex-based differences in advanced non-small cell lung cancer (aNSCLC) patients in terms of clinical-pathological and molecular features, focusing on their impact on immune response and outcome. Background: Lung cancer (LC) remains the leading cause of cancer mortality both in men and women worldwide. In the era of precision oncology, the idea of unleashing the host immune system against cancer through the development of immune checkpoint inhibitors (ICIs) radically shaped the therapeutic approach in the setting of non-oncogene addicted aNSCLC. Despite durable remissions and prolonged survival in a subset of patients, potential markers for individual prediction of immunotherapy effectiveness lacked high sensitivity and specificity. The selection of patients who could most benefit from single ICIs remains an unmet need, as well as the improvement of combination strategies for those one unresponsive or refractory to immunotherapy. Sex is a known variable that affects both innate and adaptive immune responses, as well as possibly clinical-pathological and molecular basis of LC. Although smoking is the primary risk factor for LC development in both men and women, other variable such as genetic differences, sex hormones, environmental exposures and lifestyle habit, immune system and tumor microenvironment (TME) disparities, could play an important role in sex-biased carcinogenesis and development of immune responses. Methods: An extended review of literature through PubMed was conducted, using the keywords related to patient sex (“sex”, “gender”, “male/female”, “men/women”) and NSCLC and LC epidemiological, etiological, clinical-pathological and molecular features. Conclusions: Women vs . men differences in terms of response to ICIs remain to date only suggestive, so further research, including prospective clinical trials, is warranted to establish sex as a factor in the therapeutic decision-making process. These findings about male vs. female immune