Senescent SPP1(+) macrophages remodel the tumor microenvironment and promote the progression of early-stage lung adenocarcinoma featured with mixed ground glass nodule.

Most persistent ground glass nodules (GGNs) are eventually diagnosed as early-stage lung adenocarcinoma (LUAD). Delving into the molecular underpinnings of malignant transformation of GGNs will aid in the development of preventive and therapeutic strategies to interrupt the occurrence and progression of early-stage LUAD. Macrophages (Macs) are critical in the formation of immunosuppressive tumor microenvironment (TME). However, its role in triggering the advancement of early-stage LUAD with mixed ground glass nodule (mGGN) is yet to be clarified. Utilizing scRNA-seq analysis on normal lung tissues, ground glass regions, and solid regions of mGGNs, complemented by multicolor immunohistochemistry (mIHC) and flow cytometry, we found an increase and peri-tumoral aggregation of immunosuppressive SPP1(+) alveolar Macs and monocyte-derived Macs (Mo-Macs), with a particular emphasis on the Mo-Macs. This accumulation at the tumor margin could obstruct the penetration of immune cells into the tumor's core, thereby promoting the malignant transformation of GGNs. SPP1(+) Macs not only display a senescent phenotype but also harbor the potential capacity to foster tumor metastasis and angiogenesis. Clinical data from LUAD tissue array and TCGA-LUAD database revealed a positive association between the tumoral SPP1(+) Macs percentage and poor prognosis. Furthermore, SPP1(+) Macs could reshape the TME into an immunosuppressive state through interactions with other immune cells. In vitro and in vivo assays revealed SPP1 knockout inhibited the immunosuppressive polarization and senescence of Macs, reversed the immunosuppressive status of TME and reduced the growth of LUAD xenograft tumors. Our findings propose an emerging therapeutic strategy aimed at suppressing SPP1(+) Macs, which could potentially decelerate or halt the malignant conversion of GGNs to early-stage LUAD.