Insulin-like growth factor (IGF) and its receptors IGF-1R and IGF-2R have roles in the promotion and progression of cancer, as well as in treatment resistance (Denduluri et al., 2015). Among the components of the IGF axis, IGF-1R is especially pivotal in malignancies (Hua et al., 2020). Alterations in IGF-1R activity and cross-talk of IGF-1R with pro-carcinogenic, metabolic, and anti-apoptotic pathways have been reported in several tumors, including sarcomas (Scotlandi et al., 1998), breast cancer (Obr et al., 2022, Chang et al., 2013, Surmacz et al., 1998), non-small cell lung cancer (Kim et al., 2015, Zheng et al., 2019), and brain tumors (Wang et al., 2019, Martin et al., 2022). Furthermore, IGF-1R has emerged as a therapeutic target in these tumors, and monoclonal antibodies (mAbs) (Pappo et al., 2011, Qu et al., 2017) and tyrosine kinase inhibitors (TKIs) (Chiappori et al., 2016) targeting IGF-1R have been developed. However, although these agents have garnered significant enthusiasm in the last decade, the clinical results have been poor; thus, most trials of IGF-1R inhibitors have not advanced to later stages, and the development of several drugs has been halted despite activity in preclinical studies (Jentzsch et al., 2023).

Currently, there is a re-emergence of interest in exploring combination treatments involving IGF-1R inhibitors (Schmid et al., 2023, Simpson et al., 2017). It was previously suggested that the IGF axis in carcinogenesis is more of a facilitator than a true driver (Osher and Macaulay, 2019). Therefore, with advances in precision medicine, combination drugs targeting the IGF-1R pathway and true driver alterations may be feasible, improving the efficacy of IGF-1R inhibitors in cancer and preventing resistance. The treatment strategies and developments have been heterogeneous across tumor sites; thus, a summary of the available evidence is needed. Herein, we present a review of the available preclinical and clinical data on IGF-1R inhibitors and discuss how the field could evolve.