(A) The inside story. Cetuximab binds to and inhibits EGFR, preventing binding of EGFR ligands and EGFR-dependent activation of cancer-promoting pathways. Blockade of EGFR signaling can be circumvented by crossactivation of accessory RTKs, such as FGFR, cMET, and VEGFR, GPCR signaling, or EGFR-independent activation of any signaling node downstream of EGFR. Cetuximab is being investigated in combination with agents to block other cancer-associated signaling pathways in order to boost efficacy. (B) The outside story. (i) The exposed Fc region of cetuximab bound to EGFR on tumor cells interacts with CD16 on the NK cell surface, promoting NK cell activation. (ii) Once activated, NK cells upregulate CD137 and produce IFN-γ, which promotes DC maturation. Additionally, NK activation results in cytotoxic degranulation, resulting in tumor cell lysis and the release of TAs. (iii) TAs are taken up by DCs, which present the antigens to CD8⁺ T cells (iv). Cetuximab induces both innate and adaptive immune responses. Strategies aimed to amplify the immunologic efficacy of cetuximab enhance NK cell activation, antigen processing and presentation by DCs, or T cell activation.