The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. This finding was validated in syngeneic tumor-bearing mice. The mice bearing lung metastases of CT26 colon cancer cells treated with PD-1 and/or PD-L1 inhibitors showed that the combination of anti-PD-1 and anti-PD-L1, either sequentially or simultaneously administered, caused myocarditis lesions with myocyte injury and patchy mononuclear infiltrates in the myocardium. A significant increase of infiltrating neutrophils in myocytes was noted only in mice with sequential blockade, implying a role for the pathogenesis of myocarditis. Among circulating leukocytes, concurrent and subsequent treatment of PD-1 and PD-L1 inhibitors led to sustained suppression of neutrophils. Among tumor-infiltrating leukocytes, combinatorial blockade increased CD8⁺ T cells and NKG2D⁺ T cells, and reduced tumor-associated macrophages, neutrophils, and natural killer (NK) cells in the lung metastatic microenvironment. The combinatorial treatments exhibited better control and anti-PD-L1 followed by anti-PD-1 was the most effective. In conclusion, the combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, although it gives better tumor control, and such usage should be cautionary.

Hyaluronan (HA) is essentially secreted by every cell and plays a critical role in maintaining normal cell physiology. While the structure and function of HA have been extensively investigated, questions regarding the sizes and conformation of HA under physiological and inflamed conditions, in relevance to its functions, remain elusive. In this article, we update our knowledge of the HA functional properties, including binding proteins and their signaling networks, as well as matrix formation, which can potentially induce phase separation and affect the mobility and behavior of small molecules, proteins, and cells. We detail the striking differences regarding the biological outcomes of signaling pathways for HA and membrane receptors versus HA and GPI-linked hyaluronidase Hyal-2. We describe: (1) the native, large-sized HA is not proapoptotic but signals with an overexpressed HYAL-2/WWOX/SMAD4 complex to induce apoptosis, which is likely to occur in an inflamed microenvironment; (2) HA-binding proteins are connected via signal pathway networks. The competitive binding of HA and TGF-β to the membrane HYAL-2 and the downstream HYAL-2/WWOX/SMAD4 signaling is addressed; (3) the phase-separated proteins or small molecules in the HA matrices may contribute to the aberrant interactions, leading to inflammation and disease progression; (4) the role of HA and complement C1q in Alzheimer’s disease via connection with a risk factor for Alzheimer’s disease WWOX is also discussed; (5) a hidden function is the inducible HA conformational changes that confer cancer suppression and, probably, retardation of neurodegeneration.

Radionuclides such as Rhenium‐188 (Re188) hold promise for treating metastatic cancers due to their cytotoxic effects and potential to stimulate systemic anti‐tumor immunity. However, mononuclear phagocyte system‐mediated clearance of liposome encapsulated Re188 (Lipo‐Re188) limits its tumor delivery. This study aimed to enhance the therapeutic effect of Lipo‐Re188 against lung metastases through macrophage depletion and immune checkpoint blockade. A lung metastatic colon cancer model was established via intravenous injection of CT26‐luciferase cells and then treated with Lipo‐Re188 (11.1 MBq, 30% of MTD), liposomal clodronate (Lipo‐clod) for macrophage depletion, and/or anti‐PD‐L1 antibody. Tumor progression was monitored by bioluminescence imaging, and radionuclide biodistribution was assessed at 1, 24, and 48 h post‐injection. Flow cytometry was used to assess immune cell populations in the spleen and tumor microenvironment (TME). Cytokine levels were measured using a bead‐based multiplex assay and analyzed by flow cytometry. Macrophage depletion significantly enhanced tumor accumulation of Lipo‐Re188 while reducing hepatic uptake and prolonging survival. The combination of Lipo‐clod and Lipo‐Re188 promoted B cells, restored functional T cells, and suppressed MDSC in both spleen and TME. Notably, IL‐1α and GM‐CSF levels were significantly elevated in the combination group. Triple therapy with Lipo‐clod, Lipo‐Re188, and anti‐PD‐L1 provided the greatest survival benefit, highest intratumoral B cell accumulation, and lowest interstitial macrophage levels, with no significant biological toxicity. Our study reveals that triple therapy overcomes immunosuppressive feedback and promotes a tumor‐suppressive microenvironment. These findings support a rational combination strategy integrating radiopharmaceutical therapy with immune modulation for metastatic cancer treatment.

After the publication of our review article