Somatic activating mutations in the epidermal growth factor receptor (EGFR) are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer (NSCLC)

metastatic colorectal cancer

glioblastoma

head and neck cancer

pancreatic cancer

and breast cancer. Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy

but patients inevitably experience acquired resistance. Although immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types

their efficacy is limited in cancers harboring activating gene alterations of EGFR. Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3

B7x and HHLA2

is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment (TME). In this review

we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways. Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies. We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers

as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.