Modulating tumor-associated macrophages through CSF1R inhibition: a potential therapeutic strategy for HNSCC

Tumor-associated macrophages (TAMs) are pivotal immune cells within the tumor microenvironment (TME), exhibiting dual roles across various cancer types. Depending on the context, TAMs can either suppress tumor progression and weaken drug sensitivity or facilitate tumor growth and drive therapeutic resistance. This study explores whether targeting TAMs can suppress the progression of head and neck squamous cell carcinoma (HNSCC) and improve the efficacy of chemotherapy.

Bioinformatics analyses were performed to evaluate TAMs infiltration levels in HNSCC tumor tissues and examine their associations with patients' clinicopathological characteristics and prognosis. Flow cytometry was utilized to measure the expression of key macrophage markers and assess apoptosis following treatment with colony stimulating factor 1 receptor (CSF1R) inhibitors (BLZ945, PLX3397). Additionally, immunohistochemistry was employed to detect CD68 and CD8 expression. In vivo, the antitumor efficacy of CSF1R inhibitors was tested in mouse HNSCC tumor model, both as monotherapy and in combination with cisplatin, to evaluate potential synergistic effects.

Bioinformatic analysis identified TAMs as the predominant infiltrating immune cells in the TME of HNSCC, with significantly higher infiltration levels in tumor tissues compared to adjacent non-tumor tissues. High TAMs infiltration was associated with poorer overall survival (OS), disease-free survival (DFS), human papillomavirus (HPV) infection status, and advanced disease stages. The TAMs-related genes prediction model demonstrated high prognostic accuracy. CSF1R is primarily expressed in TAMs, where high CSF1R expression may suppress antigen binding and activation. In vitro experiments showed that CSF1R inhibitors induce TAMs apoptosis, enhance their phagocytic activity, and reduce CD206 expression and IL-10 secretion, thereby diminishing their immunosuppressive function. In vivo experiments revealed that while CSF1R inhibitors alone had limited efficacy in suppressing tumor growth, their combination with cisplatin significantly enhanced therapeutic efficacy, as evidenced by increased CD8⁺ T cells infiltration within the TME.

Targeting TAMs via CSF1R inhibition enhances the therapeutic efficacy of cisplatin in HNSCC. These findings suggest that CSF1R inhibitors hold promise as a component of combination therapy for HNSCC.