Recently, research teams led by Professor Cai Songhua from the Shenzhen Branch of the Cancer Hospital of the Chinese Academy of Medical Sciences, Professor Mao Wenjun from Wuxi People's Hospital, and Professor Tang Bufu from Zhongshan Hospital affiliated to Fudan University have focused on the immune microenvironment and lung cancer radiotherapy. They demonstrated a combined therapeutic approach targeting SPP1⁺ macrophages to enhance radiotherapy sensitivity, with the findings published under the title“ SPP1⁺ TAM: CD8⁺ T cell crosstalk associates with blocking radiotherapy efficacy in lung cancer” on Research.
Citation: Jin Y, Zhuang Y, Luo P, Zhang X, Luo J, Ma Y, Guo D, Hang N, Li Q, Shen Z, et al. SPP1⁺ TAM: CD8⁺T Cell Crosstalk Associates with Blocking Radiotherapy Efficacy in Lung Cancer. Research 2025;8:Article 0851. https://doi.org/10.34133/research.0851

Research background
Radiation therapy (RT) serves as the cornerstone treatment for non-small cell lung cancer (NSCLC), with its antitumor effects primarily mediated through DNA damage induced by ionizing radiation. However, activation of DNA repair mechanisms often leads to radiation resistance. Research indicates that RT can reshape the tumor microenvironment (TME) and modulate local immune responses. Furthermore, regulating the tumor immune microenvironment may enhance tumor sensitivity to radiation, thereby improving therapeutic outcomes. Therefore, combining radiation therapy with immunomodulatory strategies could potentially boost clinical efficacy by strengthening anti-tumor immunity.
Secretory phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional cytokine-like glycoprotein involved in inflammatory responses, tissue remodeling, and immune regulation. Primarily expressed by tumor-associated macrophages (TAMs), SPP1 promotes tumor progression, angiogenesis, and invasion, with its high expression often correlating with poor prognosis in lung cancer and other malignancies. Additionally, SPP1 interacts with receptors such as CD44 and integrins to modulate T-cell function, thereby creating an immunosuppressive environment. However, the specific role of SPP1 in regulating macrophage-mediated immune responses following radiotherapy remains unclear. This study aims to investigate the effects of radiotherapy on SPP1 expression in macrophages and evaluate the therapeutic potential of SPP1-targeted therapy for radioresistance in lung cancer.
Research progress
By comparing lung cancer gene expression and localization before and after radiotherapy, the research team found that SPP1 was primarily upregulated in macrophages post-therapy. Subsequent single-cell RNA sequencing further confirmed the high expression of SPP1 in macrophages, particularly in tumor tissues (Figure 1).Cellular communication studies reveal that SPP1⁺ macrophages mediate their immunosuppressive effects through interaction with T cells via the macrophage migration inhibitory factor (MIF)-CD74–CD44/CXCR4 axis. Both single-cell RNA and bulk RNA analyses demonstrate a positive correlation between SPP1 and MIF. Prognostic analysis further indicates that patients with high expression of both SPP1⁺ macrophages and MIF exhibit significantly poorer overall survival, highlighting their potential cooperative role in promoting an immunosuppressive microenvironment.


To evaluate the therapeutic potential of combining radiotherapy (RT) with targeting SPP1⁺ macrophages, we developed a Lys^Cre-SPP1^fl/fl mouse model. The experimental mice were divided into four groups: SPP1^fl/fl, Lys^Cre-SPP1^fl/fl, SPP1^fl/fl+RT, and Lys^Cre-SPP1^fl/fl+RT. Results demonstrated that both SPP1 knockout in macrophages and radiotherapy alone suppressed tumor growth, while the combination therapy exhibited significantly stronger antitumor effects. HE staining and PCNA staining further confirmed the potent anti-tumor efficacy of the combined treatment. Additionally, SPP1 knockout in macrophages significantly reduced MIF expression and increased CD8⁺ cell expression, with these effects becoming more pronounced after radiotherapy (Figure 2). These findings indicate that targeting SPP1⁺ macrophages in combination with radiotherapy promotes local recruitment of CD8⁺T cells and enhances the anti-tumor immune response.

Future Prospects
Our research demonstrates that targeting SPP1⁺ macrophages could represent a highly promising radiosensitization strategy in non-small cell lung cancer (NSCLC) treatment. The combination of radiotherapy and SPP1-targeted intervention provides a rational pathway to overcome radiation resistance and improve clinical outcomes by alleviating macrophage-mediated immune suppression and enhancing CD8⁺T-cell infiltration. However, further studies are required to elucidate the extensive interactions between SPP1⁺ macrophages and other immune cell populations, as well as to validate the therapeutic value of this combined strategy in various NSCLC preclinical models. These findings are crucial for translating research achievements into future clinical applications.

The complete study is accessible via DOI: 10.34133/research.0851