Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches

Simple Summary This is a thorough literature review of SHP2 inhibition, its application in cancer therapy and current uses as an immune modulator. The aberrant activation of SHP2, a protein tyrosine phosphatase widely expressed in many cell types, is implicated in multiple human cancers. As SHP2 is at the crossroads of many functions and pathways, this molecule can be leveraged for therapeutic targeting in cancer. SHP2 inhibitors have shown promise in overcoming resistance to kinase inhibitors and PD-1 blockade by hindering the activation of compensatory signaling pathways. We also explore possible combinatorial approaches, wherein SHP2 inhibitors are used to overcome drug resistance, especially to immunotherapy agents. Many SHP2 inhibitors have emerged, and several have reached clinical development in solid tumors. The field is now evolving into combinatorial approaches and new delivery methods, such as SHP2 degraders.Abstract SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a protein tyrosine phosphatase widely expressed in various cell types. SHP2 plays a crucial role in different cellular processes, such as cell proliferation, differentiation, and survival. Aberrant activation of SHP2 has been implicated in multiple human cancers and is considered a promising therapeutic target for treating these malignancies. The PTPN11 gene and functions encode SHP2 as a critical signal transduction regulator that interacts with key signaling molecules in both the RAS/ERK and PD-1/PD-L1 pathways; SHP2 is also implicated in T-cell signaling. SHP2 may be inhibited by molecules that cause allosteric (bind to sites other than the active site and attenuate activation) or orthosteric (bind to the active site and stop activation) inhibition or via potent SHP2 degraders. These inhibitors have anti-proliferative effects in cancer cells and suppress tumor growth in preclinical models. In addition, several SHP2 inhibitors are currently in clinical trials for cancer treatment. This review aims to provide an overview of the current research on SHP2 inhibitors, including their mechanism of action, structure-activity relationships, and clinical development, focusing on immune modulation effects and novel therapeutic strategies in the immune-oncology field.