TGF-β derived from CAFs orchestrates a multifaceted resistance network: (1) Tumor-intrinsically, it activates SMAD4-dependent transcription of ABCB1 drug efflux pumps while suppressing pro-apoptotic Bim via HIF1α stabilization (26); (2) Immunologically, TGF-β polarizes macrophages to M2 phenotypes through SMAD3/IL-10 signaling and recruits Tregs via CCL22/CCR4 axis activation (27); (3) Stromally, it induces LOXL2-mediated collagen cross-linking that physically impedes drug penetration (28). Here, LOXL2 is linked to neoplasm.