We designed and prepared a bisphosphonate-mineralized Nano-IFNγ (Nano-IFNγ/Zole) to promote trans-differentiation of macrophages from the M2 to M1 type. Bisphosphonate in the Nano-IFNγ/Zole reduced lysosomal acidification by inhibiting isoprene modification of Rab family proteins, enhanced tumor antigen cross-presentation and activated the TFEB pathway. These mechanisms, in conjunction with IFNγ-activated JAK/STAT1 signaling, facilitated the trans-differentiation of macrophages.