Compared with most other antitumor platforms, tumor-targeting bacteria have many advantages in inhibiting tumor growth. For example, bacteria have a strong tropism to different types of cancers, proliferate and penetrate within tumor tissues, and initiate antitumor immune responses. Based on clinical needs, bacteria can be further programmed through genetic manipulation or specific synthetic bioengineering to produce and deliver anticancer drugs. Live bacteria-based therapeutics approaches can be applied in combination with other antitumor therapies to achieve better clinical results.
Tumor-targeting bacteria can be engineered to deliberately express cytolytic anticancer payloads in a tumor-specific manner. Importantly, in order to reduce cytotoxicity caused by anticancer payloads, the inducible gene expression strategies can produce anticancer drugs only inside cancer tissue. Consequently, genetically engineered SAM2 successfully deliver cytolytic payloads to tumor cells and resulted in the subsequent release of danger signals from dying cancer cells.
Immune adjuvant-secreting bacteria exert enhanced tumor-suppressive effects through two-step activation of TLR4 and TLR5 signaling pathways. First, bacterial colonization of tumors increased the infiltration and activation of immune cells via TLR4 signaling. Second, the recruited immune cells were further activated by the TLR5 signaling triggered by in situ–secreted immune adjuvant in the same microenvironment. These results provide a strong potential for nonvirulent tumor-targeting bacteria releasing multiple TLR ligands to be used as high-efficiency cancer immunotherapy.
This engineered bacteria co-expressing multiple therapeutic payloads induce diverse danger signals from cancer cells and strongly increase the anticancer immune response by activations of immune effector cells such as antigen presenting cells (APCs), CD4+, CD8+ effector T cells, or memory T cells in tumors. Moreover, these signals induced by SAM4 elicit prophylactic antitumor immunity in a vaccine model. Thus, engineered bacteria with multifunctional anticancer effects enabled effective tumor ablation and prophylactic vaccination.