Bimetallic rare earth nanoplatform amplifies DNA damage to trigger necroptosis and immune cascade for potent durable antitumor therapy

Immunotherapy is an innovative cancer treatment harnessing the immune system to specifically eliminate tumor cells, but tumor immune evasion and drug resistance often lead to temporary remission rather than a radical cure. Inducing DNA damage is a promising approach to enhance immunotherapeutic efficacy. Herein, we constructed pH-responsive methotrexate (MTX)-loaded bimetallic rare earth hydroxide nanoparticles (YMn(OH)_x@MTX NPs). These nanomaterials controllably release Y³⁺, Mn²⁺, and MTX in the acidic tumor microenvironment and within lysosomes, significantly inducing organelle and DNA damage in tumor cells and activating receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. MTX inhibits dihydrofolate reductase (DHFR) activity, leading to reduced tetrahydrofolate (THF) production. This suppresses tumor DNA replication, blocks the repair of damaged DNA, and amplifies nanomaterial-induced initial DNA damage, further intensifying necroptosis. Moreover, damage-associated molecular patterns (DAMPs) released by necroptotic tumor cells, along with intracellular free DNA and Mn²⁺, act synergistically to activate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and trigger innate immunity. This "innate-adaptive immunity" synergy reprograms the immunosuppressive tumor microenvironment, affording potent and durable antitumor therapy. Collectively, this rare earth-based nanoplatform acts through multi-pathway synergy, offering innovative insights for advanced antitumor strategies. STATEMENT OF SIGNIFICANCE: This study innovatively constructs a pH-responsive bimetallic rare earth nanoplatform. Via a dual synergistic strategy of direct DNA damage induction and damage amplification, it triggers RIPK3-MLKL-mediated necroptosis. Released by dying tumor cells, damage-associated molecular patterns (DAMPs), together with intracellular free DNA and Mn²⁺ released from the nanoplatform, synergistically activate the cGAS-STING pathway, initiating immune responses. This overcomes the challenges of tumor immune evasion and drug resistance, breaking the limitations of traditional single-mode therapy. This multi-pathway synergistic design offers a new paradigm for cancer treatment, allowing readers to intuitively appreciate the charm of interdisciplinary innovation between nanotechnology and tumor immunology and inspiring scientific research ideas.