Smart nanomaterials targeting spatially heterogeneous immunosuppressive niches to reverse ovarian cancer resistance and enhance immune checkpoint therapy

Immunotherapy resistance remains a major barrier in ovarian cancer (OC), arising from interconnected mechanisms that include immune checkpoint dysregulation, metabolic reprogramming, aberrant DNA repair, signaling plasticity, and spatially heterogeneous tumor microenvironments. In particular, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis activation intersects with non-immune resistance pathways and metabolic remodeling, forming a self-reinforcing network that limits therapeutic durability. Recent advances in nanotechnology offer new opportunities to precisely modulate these resistance circuits. This review integrates multi-omics strategies, including single-cell and spatial transcriptomic profiling, to illustrate how resistance-associated nodes can be systematically identified and translated into mechanism-informed nanocarrier design. We summarize emerging smart nanomaterials capable of targeting immunosuppressive cell populations, regulating metabolic-immune crosstalk, and coordinating combination interventions such as immune checkpoint inhibitors (ICIs), nucleic acid therapeutics, and metabolic modulators. Furthermore, adaptive nanoplatforms featuring stimulus-responsive release, microenvironment remodeling, and feedback-guided modulation are discussed as components of an evolving “omics-target-delivery” closed-loop framework. Collectively, these advances position intelligent nano-enabled immune modulation as a promising systems-level strategy to overcome low response rates and limited durability of immunotherapy in OC.