Tumor Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas

Sarcomas are a heterogeneous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases make treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which leads to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher toxic doses of chemotherapy. In this study, we tested the mechanotherapeutic ketotifen combined with either pegylated liposomal doxorubicin (PLD) or pegylated liposomal coencapsulated alendronate-doxorubicin (PLAD) plus anti-programmed cell death protein 1 antibody in mouse models of fibrosarcoma and osteosarcoma. We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave elastography and contrast-enhanced ultrasound, respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. Furthermore, we observed a trend toward improved antitumor responses when nano-chemotherapy is given alongside anti-programmed cell death protein 1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper cells, and decreased the number of regulatory T cells. In addition, the combination also altered the polarization of tumor-associated macrophages, favoring the M1 immune-supportive phenotype over the M2 immunosuppressive phenotype. Collectively, our findings provide evidence that ketotifen-induced TME reprogramming can improve the efficacy of nanomedicine-based chemo-immunotherapy in sarcomas.