The efficacy and off-target effects of immune checkpoint inhibitors (ICI) in cancer treatment vary among patients. Monocytes likely contribute to this heterogeneous response due to their crucial role in immune homeostasis. We conducted a systematic review and meta-analysis to evaluate the impact of monocytes on ICI efficacy and immune-related adverse events (irAEs) in patients with cancer. We systematically searched PubMed, Web of Science, and Embase for clinical studies from January 2000 to December 2023. Articles were included if they mentioned cancer, ICI, monocytes, or any monocyte-related terminology. Animal studies and studies where ICIs were combined with other biologics were excluded, except for studies where two ICIs were used. This systematic review was registered with PROSPERO (CRD42023396297) prior to data extraction and analysis. Monocyte-related markers, such as absolute monocyte count (AMC), monocyte/lymphocyte ratio (MLR), specific monocyte subpopulations, and m-MDSCs were assessed in relation to ICI efficacy and safety. Bayesian meta-analysis was conducted for AMC and MLR. The risk of bias assessment was done using the Cochrane-ROBINS-I tool. Out of 5787 studies identified in our search, 155 eligible studies report peripheral blood monocyte-related markers as predictors of response to ICI, and 32 of these studies describe irAEs. Overall, based on 63 studies, a high MLR was a prognostic biomarker for short progression-free survival (PFS) and overall survival (OS) hazard ratio (HR): 1.5 (95% CI: 1.21-1.88) and 1.52 (95% CI:1.13-2.08), respectively. The increased percentage of classical monocytes was an unfavorable predictor of survival, while low baseline rates of monocytic myeloid-derived suppressor cells (m-MDSCs) were favorable. Elevated intermediate monocyte frequencies were associated but not significantly correlated with the development of irAEs. Baseline monocyte phenotyping may serve as a composite biomarker of response to ICI
however, more data is needed regarding irAEs. Monocyte-related variables may aid in risk assessment and treatment decision strategies for patients receiving ICI in terms of both efficacy and safety.