The use of immune checkpoint inhibitors (ICIs) has achieved remarkable success in the treatment of patients with advanced tumours across various types of cancers [1]. However, due to the existence of multiple mechanisms of resistance to ICIs therapy in different tumours, and the high heterogeneity of these resistance mechanisms in different populations within the same tumour, the efficacy of ICIs therapy varies greatly among different patients, with only a fraction of patients who can achieve sustained efficacy [2], [3]. Therefore, it is pivotal to find a robust predictor that can predict the therapeutic efficacy of ICIs therapy. Currently, many studies have reported predictors that can predict the efficacy of ICIs therapy, such as tumour mutation burden (TMB) and the expression level of PD-L1; however, these predictors generally have limitations, including high cost, poor predictive ability, and lack of standardized cut-off values [4]. Therefore, finding novel predictive markers that can accurately anticipate the efficacy of ICIs therapy remains an urgent task.

The rearranged during transfection (RET) gene, which encodes a transmembrane receptor tyrosine kinase, is a proto-oncogene with paramount importance in tumour proliferation, migration, and invasion [5], [6]. Activation of RET signalling pathway triggers classical oncogenic pathways encompassing PI3K/AKT, RAS/MAPK, RAS/ERK, and JNK [7], [8], [9], [10], [11], [12]. Aberrant RET signalling pathway activation, predominantly attributed to RET fusion or mutation, is causally linked to the onset and progression of diverse malignancies. Gain-of-function RET mutations drive tumourigenesis and development of Multiple Endocrine Neoplasia Type 2 (MEN 2) [6]. In contrast, RET fusion-mediated abnormal RET signalling pathway activation has a significant involvement in the tumourigenesis and development of papillary thyroid carcinoma (PTC), non-small cell lung cancer (NSCLC), and various other cancer types [13]. Moreover, RET signalling pathway has a significant involvement in tumour immunity. RET expression may influence tumour progression in a wider range of cancers by promoting tumour-associated inflammation, a process involved in tissue remodelling, local invasion, and metastatic disease [6]. RET activation stimulates pro-inflammatory patterns of chemokine and cytokine expression in several tumour types [14], [15], [16], which can recruit immune cells to the tumour microenvironment (TME) to promote matrix degradation, angiogenesis and tumour growth. Furthermore, RET and its co-receptors are extensively expressed on members of the immune system such as B cells, T cells, NK cells, monocytes and macrophages [17], suggesting that pro-inflammatory patterns could be further stimulated by the activation of RET signalling on both tumour and immune cells in TME. Accordingly, genetic status of RET has a significant involvement in tumour immunity and might be able to predict the effectiveness of immunotherapy. However, the relationship between genomic alterations of RET and ICIs response has not yet been clearly investigated.

In this study, we focused on RET mutations and conducted a comprehensive analysis to assess the predictive effect of RET mutations on the therapeutic efficacy of ICIs in cancer treatment. Our research demonstrated that RET mutation was associated with better clinical outcomes and promoted anti-tumour immunity among multiple cancer types treated by ICIs.