The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided an alternative strategy involved the orderly treatment of TLR3 agonist polyinosine–polycytidylic acid (PIC) and low-dose cisplatin. The optimal dose of cisplatin, the novel role of PIC and the side effects of the combined chemotherapy were determined in vitro and in distinct human tumor models in vivo. The results in vitro indicated that preculture with PIC downregulated drug transporters (e.g., P-gp and MRP-1) and increased the cytoplasmic residence of cisplatin, and dramatically strengthened the low-dose cisplatin-induced cell death in TLR3- and caspase-3–dependent manner. Meanwhile, the spleen immunocytes were activated but the immunosuppressive cancer-associated fibroblasts (CAF) were dampened. These findings were confirmed in human tumor models in vivo. Pretreatment with PIC promoted the low-dose cisplatin residence for tumor regression with decreased myeloid-suppressive cells (MDSC), tumor-associated macrophages (TAM) and CAFs, and alleviated adverse side effects in the OSCC model, which was further enhanced by the Cetuximab safely. This strategy also repressed the progression of melanoma and lymphoma. Moreover, TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, which was upregulated during this chemotherapy. Knockdown of lnc-IL7R improved the chemotherapy sensitivity. Overall, this study provided preclinically new instructions for the PIC/cisplatin utilization to target tumor microenvironment and strengthen the low-dose cisplatin-based chemotherapy with reduced side effects. Mol Cancer Ther; 16(6); 1068–79. ©2017 AACR.
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