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Background <p>Radiotherapy (RT) has been shown to elicit antitumor immune responses, yet it rarely induces durable systemic immunity. The identification of immune checkpoints that constrain RT-induced immune activation remains an unmet clinical need.</p> Methods <p>Using genetic deletion, pharmacologic blockade, syngeneic bilateral and orthotopic murine non–small cell lung cancer (NSCLC) models, and single-cell RNA sequencing, we dissected the role of CD24 in RT-induced immune responses.</p> Results <p>CD24 was overexpressed across NSCLC stages with stage-dependent bidirectional prognostic significance. CD24 exerted no tumor-intrinsic proliferative effects in vitro but drove macrophage-dependent immune evasion in vivo. Combined RT and CD24 blockade synergistically remodeled the tumor microenvironment—augmenting M1-polarised macrophages while suppressing M2 macrophages, regulatory T cells, and PMN-MDSCs—and induced reproducible abscopal responses across bilateral, orthotopic, and metastatic models regardless of radiation modality. Macrophage depletion abolished both local and distant tumor control, whereas CD8⁺ T cell depletion caused only partial attenuation, establishing macrophages as essential initiators of systemic immunity. Single-cell transcriptomics revealed that RT-induced CCL2 recruits peripheral CCR2⁺ monocytes that CD24 blockade reprograms into inflammatory macrophages; CCL2 neutralization completely abrogated the abscopal effect. Incorporating PD-1 blockade further amplified effector T cell responses and conferred durable tumor-specific immune memory.</p> Conclusions <p>CD24 is a critical innate immune checkpoint restraining RT-induced systemic antitumor immunity. Combined RT, CD24 blockade, and PD-1 inhibition drives a macrophage-initiated, CCL2–CCR2-dependent innate-to-adaptive immune cascade, providing a mechanistic rationale for this combination strategy in NSCLC.</p>

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Radiotherapy synergizes with CD24 blockade to initiate macrophage-driven systemic antitumor immunity in non–small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Gongjun Wang,
  • Shuo Yuan,
  • Fuhao Xu,
  • Deli Mao,
  • Tao Hu,
  • Qixin Xu,
  • Li Li,
  • Zhihao Wei,
  • Shuanghu Yuan

摘要

Background

Radiotherapy (RT) has been shown to elicit antitumor immune responses, yet it rarely induces durable systemic immunity. The identification of immune checkpoints that constrain RT-induced immune activation remains an unmet clinical need.

Methods

Using genetic deletion, pharmacologic blockade, syngeneic bilateral and orthotopic murine non–small cell lung cancer (NSCLC) models, and single-cell RNA sequencing, we dissected the role of CD24 in RT-induced immune responses.

Results

CD24 was overexpressed across NSCLC stages with stage-dependent bidirectional prognostic significance. CD24 exerted no tumor-intrinsic proliferative effects in vitro but drove macrophage-dependent immune evasion in vivo. Combined RT and CD24 blockade synergistically remodeled the tumor microenvironment—augmenting M1-polarised macrophages while suppressing M2 macrophages, regulatory T cells, and PMN-MDSCs—and induced reproducible abscopal responses across bilateral, orthotopic, and metastatic models regardless of radiation modality. Macrophage depletion abolished both local and distant tumor control, whereas CD8⁺ T cell depletion caused only partial attenuation, establishing macrophages as essential initiators of systemic immunity. Single-cell transcriptomics revealed that RT-induced CCL2 recruits peripheral CCR2⁺ monocytes that CD24 blockade reprograms into inflammatory macrophages; CCL2 neutralization completely abrogated the abscopal effect. Incorporating PD-1 blockade further amplified effector T cell responses and conferred durable tumor-specific immune memory.

Conclusions

CD24 is a critical innate immune checkpoint restraining RT-induced systemic antitumor immunity. Combined RT, CD24 blockade, and PD-1 inhibition drives a macrophage-initiated, CCL2–CCR2-dependent innate-to-adaptive immune cascade, providing a mechanistic rationale for this combination strategy in NSCLC.