Tumor vaccines that induce effective and sustained antitumor immunity are highly promising for
cancer therapy. However, the antitumor potential of these
vaccines is weakened due to the immunosuppressive characteristics of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells within the TME; they play an important role in
tumor growth,
metastasis, immunosuppression, and drug resistance. Fibroblast activation
protein-α (FAP) is overexpressed in CAFs in more than 90% of human
tumor tissues. Further, FAP+CAFs are an ideal interstitial target for the
immunotherapy of solid
tumors. Exosomes derived from
tumor cells contain many
tumor antigens, which can be used as the basis of
tumor vaccines that elicit strong antitumor immunity. Almost all exosome-based
cancer vaccines have been designed and developed for
tumor parenchymal cells. Moreover, the exosome production is very low and the purification is very difficult, limiting their clinical application as
tumor vaccines. In this study, we developed FAP gene-engineered
tumor cell-derived exosome-like nanovesicles (eNVs-FAP) as a
tumor vaccine that can be prepared easily and in large quantities. The eNVs-FAP
vaccine inhibited
tumor growth by inducing strong and specific cytotoxic T lymphocyte (CTL) immune responses against
tumor cells and FAP+CAFs and reprogramming the immunosuppressive TME in the colon,
melanoma, lung, and
breast cancer models. Moreover, eNVs-FAP
vaccine-activated cellular immune responses could promote
tumor ferroptosis by releasing
interferon-gamma (IFN-γ) from CTLs and depleting FAP+CAFs. Thus, eNVs-FAP is a candidate
tumor vaccine targeting both the
tumor parenchyma and the stroma. STATEMENT OF SIGNIFICANCE:
Nanovaccines can activate immune cells and promote an antitumor immune response. In this study, we developed the fibroblast activation
protein-α (FAP) gene-engineered
tumor cell-derived exosome-like vesicle
vaccines (eNVs-FAP). A large number of eNVs-FAP were obtained by continuously squeezing FAP gene-engineered
tumor cells. eNVs-FAP showed excellent antitumor effects in a variety of
tumor-bearing mouse models. The mechanistic analysis showed that eNVs-FAP promoted the maturation of dendritic cells (DCs), increased the infiltration of effector T cells into target
tumor cells and FAP-positive cancer-associated fibroblasts (FAP+CAFs), and reduced the proportion of immunosuppressive cells, including M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), in the tumor microenvironment (TME). Moreover, the clearance of FAP+CAFs helped enhance
interferon-gamma-induced
tumor cell ferroptosis.