Abstract Background: CD47, a “don’t eat me” signal, enables tumor cells to evade macrophage-mediated clearance. EGFR-mutant non-small cell lung cancer (NSCLC) exhibits increased CD47 expression, facilitating immune evasion by inhibiting phagocytosis. Preclinical studies suggest that combining third-generation EGFR TKIs with CD47 blockade can enhance antitumor immunity. Here, we investigated the therapeutic potential of combining the anti-CD47 antibody IMC-002 with lazertinib to enhance macrophage phagocytosis. Methods: EGFR-mutant and wild-type NSCLC cell lines, patient-derived cells (PDCs), and TKI-resistant derivatives were analyzed for CD47 expression by qPCR, immunoblotting, and flow cytometry. Cells were treated with lazertinib and IMC-002 individually or in combination across a concentration range. Macrophage phagocytosis was quantified by flow cytometry and live-cell imaging (Incucyte). Single-cell RNA sequencing (scRNA-seq) datasets from EGFR-mutant NSCLC patients before and after TKI treatment were analyzed to characterize changes in CD47 expression and resistance-associated pathways. Results: EGFR-mutant cell lines showed overall higher baseline CD47 expression compared to wild-type controls. Lazertinib treatment induced a dose-dependent increase in surface CD47 expression in H1975 cells. Co-treatment with lazertinib and IMC-002 led to additive to synergistic increases in macrophage-mediated phagocytosis in multiple EGFR-mutant cell lines and in PDCs. In cell lines where lazertinib upregulated surface CD47, IMC-002 blockade elicited substantially greater phagocytosis than lazertinib alone, suggesting that TKI exposure increases target availability and that subsequent antibody blockade acts synergistically by abrogating CD47-SIRPα signaling and promoting macrophage-mediated engulfment. scRNA-seq analyses of EGFR-mutant NSCLC patients before and after third-generation EGFR TKI treatment revealed increased CD47 expression within tumor clusters enriched for drug-tolerant persister signatures, including TGF-β, Wnt, and YAP pathways, providing additional explanations for enhanced anti-CD47 antibody accessibility and phagocytic clearance following combination treatment. Collectively, EGFR-TKI exposure can increase the abundance and accessibility of CD47 on tumor cells, and anti-CD47 antibody treatment synergizes with lazertinib to amplify macrophage-mediated clearance, supporting a rationale for a combination strategy to improve antitumor immunity in EGFR-mutant NSCLC. Conclusion: Lazertinib induces CD47 upregulation and synergizes with IMC-002 to enhance macrophage-mediated clearance of EGFR-mutant NSCLC cells. These findings provide a mechanistic rationale for clinical evaluation of EGFR-TKI and anti-CD47 combination strategies to improve therapeutic efficacy in EGFR-mutant lung cancer. Citation Format: Myungja Ro, Seung Min Yang, Youngtaek Kim, Min-Hak Lee, Eun Ji Lee, JuHyeon Lee, Mi Ran Yun, Ji-Eun Park, Jiyea Choi, Hyesun Lee, Sung Ho Kim, Heung Tae Kim, Byoung Chul Cho. EGFR-TKI enhances anti-CD47 antibody-mediated macrophage phagocytosis in EGFR-mutant non-small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7745.
Ro et al. (Fri,) studied this question.