Lactic acid (LA) plays a major role in the occurrence, development, and spread of cancer. Enlightened by its high accumulation in tumor site, a novel lactate oxidase (LOD) conjugated two-dimensional Pd@Ir nanoplatform (Pd@Ir-LOD, PIL) was fabricated to combine cascade reaction with photothermal for tumor therapy. In detail, the overexpressed LA in tumor microenvironment (TME) was a key factor to activate the PIL-based cascade reaction: (1) Plenty of H₂O₂ could be generated from LA by the catalysis of LOD with O₂; (2) potent ·OH was produced from H₂O₂ due to the peroxidase (POD)-like activity of PIL; (3) meantime, PIL’s catalase (CAT)-like activity could decompose part H₂O₂ into O₂ to achieve the purpose of LA cyclic oxidization. Moreover, the reduced glutathione (GSH) scavenging capability of PIL might protect the produced reactive oxygen species (ROS) from being cleared to further improve the cascade therapeutic effect. More importantly, PIL had excellent photothermal conversion efficiency (37.35%) and manifested a surprising temperature rising effect in tumor. Taken together, the decreasing LA concentration, accumulation of high-toxic ROS, the depletion of GSH together with the higher intra-tumoral temperature potently enhanced in vivo antitumor therapy. Therefore, a promising therapeutic tactic based on PIL integrating endogenous LA consumption, chemodynamic therapy (CDT), and photothermal therapy (PTT) has been put forward.

Targeted radionuclide therapy (TRT) provides an immunogenic microenvironment for immune checkpoint inhibitor (ICI) therapy by inducing DNA double-strand break, activating the cGAS-STING, NF-κB/IRF3 and STAT1/3-IRF1 pathways, up-regulating the expression of PD-L1, and increasing the infiltration of pro-inflammatory cytokines, CD8⁺ T cells and CD4⁺ T cells in tumors. The combined therapy could increase the infiltration of memory effector T cells, M1 macrophages and dendritic cells which positively regulate immune response, and downregulate immunosuppressive regulatory T cells, M2 macrophages and myeloid-derived suppressor cells. Partial complete remission and immune memory were achieved in tumor-bearing mice treated with combined therapy. It is worth noting that radiodiagnostic agent 2-[¹⁸F]FDG combined with anti-PD-L1 mAb could also reprogram the immune microenvironment and significantly improve therapeutic effect. This review presents typical combination therapy strategies, emphasizes the time window of combination therapy and different combinations of therapy that may improve the therapeutic effect, and proposes that radiodiagnostic agents combined with tumor immunotherapy are expected to become a new paradigm and a direction for further research in the future.