A novel strategy using IR-TAM@Alb nanoparticles has been developed to enhance radiotherapy (RT) and inhibit radiation-induced pulmonary fibrosis (RIPF). IR-TAM@Alb is a nanoparticle composed of a mitochondria-targeted heptamethine cyanine dye (IR-68) conjugated with Tamoxifen (TAM), which inhibits oxidative phosphorylation (OXPHOS). This nanoparticle effectively targets tumors and RIPF areas, reversing tumor hypoxia, suppressing PD-L1 and TGF-β expression, and inhibiting fibrosis development. The study demonstrates that IR-TAM@Alb enhances RT efficacy by increasing DNA damage, promoting T cell infiltration, and reducing immune resistance. Additionally, it suppresses RIPF by inhibiting TGF-β secretion, collagen production, and fibronectin deposition. In vivo experiments show that IR-TAM@Alb significantly reduces tumor growth, prevents metastasis, and alleviates fibrosis. The nanoparticles also exhibit selective accumulation in RIPF areas, making them effective for both tumor treatment and fibrosis prevention. This dual-targeting approach offers a promising strategy for improving RT outcomes and reducing complications like RIPF. The study highlights the potential of IR-TAM@Alb as a multifunctional nanomedicine for enhancing tumor immunotherapy and preventing fibrosis.A novel strategy using IR-TAM@Alb nanoparticles has been developed to enhance radiotherapy (RT) and inhibit radiation-induced pulmonary fibrosis (RIPF). IR-TAM@Alb is a nanoparticle composed of a mitochondria-targeted heptamethine cyanine dye (IR-68) conjugated with Tamoxifen (TAM), which inhibits oxidative phosphorylation (OXPHOS). This nanoparticle effectively targets tumors and RIPF areas, reversing tumor hypoxia, suppressing PD-L1 and TGF-β expression, and inhibiting fibrosis development. The study demonstrates that IR-TAM@Alb enhances RT efficacy by increasing DNA damage, promoting T cell infiltration, and reducing immune resistance. Additionally, it suppresses RIPF by inhibiting TGF-β secretion, collagen production, and fibronectin deposition. In vivo experiments show that IR-TAM@Alb significantly reduces tumor growth, prevents metastasis, and alleviates fibrosis. The nanoparticles also exhibit selective accumulation in RIPF areas, making them effective for both tumor treatment and fibrosis prevention. This dual-targeting approach offers a promising strategy for improving RT outcomes and reducing complications like RIPF. The study highlights the potential of IR-TAM@Alb as a multifunctional nanomedicine for enhancing tumor immunotherapy and preventing fibrosis.