CCL5 hi Macrophages Interact with CD8 + T Cells and Potentiate Responsiveness to PD‐1 Blockade Plus Chemotherapy in Esophageal Squamous Cell Carcinoma

Abstract Immunotherapy has significantly transformed cancer therapy and reinvigorated research in cancer immunology. Several clinical trials have employed neoadjuvant immunochemotherapy (NIC) for advanced esophageal squamous cell carcinoma (ESCC), resulting in significant benefits for many patients. However, response rates remain limited, underscoring the need for more effective screening methods and novel therapeutic strategies. Tumor‐associated macrophages (TAMs) have been shown to play a crucial role in tumor progression and impact the clinical outcomes of cancer patients. Nonetheless, it is worth noting that TAMs exhibit phenotypic and functional heterogeneity. In this study, a distinct population of CCL5 hi macrophages is identified that plays a critical role in ESCC when treated with immunochemotherapy. Furthermore, insights are gained into the underlying mechanisms, revealing the existence of a feedback loop involving IFN‐γ, CCL5 hi macrophages, and CD8 + T cells within the tumor microenvironment of ESCC undergoing immunochemotherapy. Specific signatures associated with CCL5 hi macrophages are correlated with a better response to immunochemotherapy in patients with ESCC. Moreover, the in vivo experiments demonstrate that CCL5 supplementation enhances the effectiveness of immunochemotherapy. This research contributes to the optimization of patient stratification and provides a rationale for novel combinatorial approaches involving immunotherapy in the treatment of ESCC.