Thyroid cancer-derived exosomal SPP1 promotes tumor progression by driving macrophage M2 polariza… — Organogenesis (2026)

Resumo clínico (PT)

Estudo pré-clínico que caracteriza o papel do SPP1 transportado por exossomas de carcinoma da tiroide na polarização M2 de macrófagos e progressão tumoral. Exossomas de linha TPC1 enriquecidos em SPP1 induziram fenótipo M2 e promoveram proliferação, migração e invasão; o knockdown de SPP1 aboliu estes efeitos. O mecanismo proposto passa pela ligação a CD44 com activação de JAK2/STAT3; o bloqueio de CD44 reverteu a polarização e o efeito pró-tumoral. Em modelo xenoenxerto, exossomas com SPP1 diminuído reduziram crescimento tumoral e infiltração M2. Trabalho ainda experimental, mas aponta o eixo exossomal SPP1–CD44 como alvo terapêutico potencial em onco-endocrinologia da tiroide.

Abstract (original)

While secreted phosphoprotein 1 (SPP1) drives macrophage M2 polarization and cancer progression in multiple malignancies, its role in thyroid cancer remains poorly understand. This study investigated the roles and mechanisms of thyroid cancer-derived exosomal SPP1 in regulating macrophage M2 polarization and malignant progression in thyroid cancer. SPP1 protein expression in thyroid cancer tissues and cell lines was assessed. Exosomes from TPC1 cells were isolated and characterized for SPP1 expression. THP-1 cell-differentiated M0 macrophages were treated with unmodified or SPP1-knockdown exosomes, followed by detection of M2 phenotype markers and analysis of cytokine secretion profiling in response to LPS stimulation. The conditioned macrophages were then co-cultured with thyroid cancer cells, and cell proliferation, migration and invasion were examined. Mechanistic studies focused on CD44/JAK2/STAT3 signaling using an anti-CD44 monoclonal antibody. Additionally, tumor growth and macrophage infiltration were assessed in a xenograft tumor mouse model following exosomal SPP1 knockdown. SPP1 was upregulated in thyroid cancer and enriched in TPC1-derived exosomes. These exosomes induced macrophage M2 polarization, thereby promoting cancer cell proliferation, migration and invasion. However, SPP1 knockdown in exosomes abolished these effects. Exosomal SPP1 directly interacted with CD44 receptors and activated the JAK2/STAT3 signaling pathway to drive M2 polarization. CD44 blockade reversed M2 polarization and pro-tumorigenic effects. SPP1-deficient exosomes reversed tumor growth and attenuated M2 macrophage infiltration in xenograft model. Thyroid cancer-derived exosomal SPP1 promotes tumor progression by driving macrophage M2 polarization via the CD44/JAK2/STAT3 signaling pathway. The exosomal SPP1-CD44 axis represents a promising therapeutic target for thyroid cancer.