Tumor-Microenvironment-Activatable Nanoparticle Mediating Immunogene Therapy and M2 Macrophage-Targeted Inhibitor for Synergistic Cancer Immunotherapy

Abstract

Immunotherapy has achieved prominent clinical efficacy in combating cancer and has recently become a mainstream treatment strategy. However, achieving broad efficacy with a single modality is challenging, and the heterogeneity of the tumor microenvironment (TME) restricts the accuracy and effectiveness of immunotherapy strategies for tumors. Herein, a TME-responsive targeted nanoparticle to enhance antitumor immunity and reverse immune escape by codelivering interleukin-12 (IL-12) expressing gene and colonystimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (PLX) is presented. The introduction of disulfide bonds and cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) peptides conferred reduction reactivity and tumor targeting to the nanoparticles, respectively. It is hypothesized that activating host immunity by the local expression of IL-12, while modulating the tumor-associated macrophages (TAM) function through blocking CSF-1/CSF-1R signaling, could constitute a feasible approach for cancer immunotherapy. The fabricated functional nanoparticle successfully ameliorated the TME by stimulating the proliferation and activation of T lymphocytes, promoting the repolarization of TAMs, reducing myeloid-derived suppressor cells (MDSCs), and promoting the maturation of dendritic cells (DC) as well as the secretion of antitumor cytokines, which efficiently suppressed tumor growth and metastasis. Finally, substantial changes in the TME were deciphered by single-cell analysis including infiltration of different cells, transcriptional states, secretory signaling and cell−cell communications. These findings provide a promising combinatorial immunotherapy strategy through immunomodulatory nanoparticles.

New Strategies for Macrophage Re-Education in Cancer: An Update

“…Moreover, the authors demonstrated in vivo, in a mouse transgenic model, the ability of senescent and tumor thyroid cells to recruit and polarize macrophages in the M2-like TAM pro-tumor phenotype and, in turn, TAM allow tumor progression [ 101 ]. Another very recent study demonstrated that the association of the CSF-1R inhibitor, PLX3397 (PLX), with the cytokine IL-12, which has the ability to stimulate the host’s immune activity, promoted repolarization of TAM, stimulated the proliferation and activation of T lymphocytes, reduced MDSCs recruitment, and suppressed tumor growth and metastasis [ 102 ] ( Table 4 ). Cytokines/chemokines are largely produced by CAFs in the TME having a role in the crosstalk between macrophages and cancer cells, as stated above.…”