In the past decade, bacteria‐based cancer immunotherapy has attracted much attention in the academic circle due to its unique mechanism and abundant applications in triggering the host anti‐tumor immunity. One advantage of bacteria lies in their capability in targeting tumors and preferentially colonizing the core area of the tumor. Because bacteria are abundant in pathogen‐associated molecular patterns that can effectively activate the immune cells even in the tumor immunosuppressive microenvironment, they are capable of enhancing the specific immune recognition and elimination of tumor cells. More attractively, during the rapid development of synthetic biology, using gene technology to enable bacteria to be an efficient producer of immunotherapeutic agents has led to many creative immunotherapy paradigms. The combination of bacteria and nanomaterials also displays infinite imagination in the multifunctional endowment for cancer immunotherapy. The current progress report summarizes the recent advances in bacteria‐based cancer immunotherapy with specific foci on the applications of naive bacteria‐, engineered bacteria‐, and bacterial components‐based cancer immunotherapy, and at the same time discusses future directions in this field of research based on the present developments.

The tumor immunosuppressive microenvironment greatly limits the efficacy of immunotherapy. Tumor-associated macrophages (TAMs) are the most abundant immunosuppressive cells in the tumor microenvironment, which can inhibit the tumor after converting it to an M1-like phenotype. In addition, immunogenic cell death (ICD) can increase the amount of T lymphocytes in tumors, activating antineoplastic immunity. Herein, tumor-associated macrophage polarization therapy supplemented with PLGA-DOX (PDOX)-induced ICD is developed for cancer treatment. The nanoparticles/bacteria complex (Ec-PR848) is fabricated for tumor targeting and TAM polarization, and PLGA-R848 (PR848) are attached to the surface of Escherichia coli (E. coli) MG1655 via electrostatic absorption. The toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) and E. coli can greatly polarize M2 macrophages to M1 macrophages, while PDOX-induced ICD can also impair the immunosuppression of the tumor microenvironment. This strategy shows that tumor-associated macrophage polarization therapy combined with ICD induced by low-dose chemotherapeutic drugs can commendably enhance the efficacy of immunotherapy.

The checkpoint inhibitor therapy that blocks programmed death‐1 (PD‐1) and its major ligand PD‐L1 has achieved encouraging clinical efficacy in certain cancers. However, the binding of checkpoint inhibitors with other immune cells that express PD‐L1 often results in a low response rate to the blockade and severe adverse effects. Herein, an LyP1 polypeptide‐modified outer‐membrane vesicle (LOMV) loaded with a PD‐1 plasmid is developed to achieve self‐blockade of PD‐L1 in tumor cells. The nanocarriers accumulate in the tumor tissue through OMV‐targeting ability and are internalized into the tumor cells via the LyP1‐mediated target, subsequently delivering PD‐1 plasmid into the nucleus, leading to the expression of PD‐1 by the tumor cells. In addition, a magnetic particle chemiluminescence kit is developed to quantitatively detect the binding rate of PD‐1/PD‐L1. The self‐expressed PD‐1 bonded with the PD‐L1 is expressed by both autologous and neighboring tumor cells, achieving self‐blockade. Simultaneously, the outer‐membrane protein of LOMV recruits cytotoxic lymphocyte cells and natural killer cells to tumor tissues and stimulates them to secrete IFN‐γ  , improving the antitumor activity of the PD‐1/PD‐L1 self‐blocking therapy.

A cancer vaccine has been widely applied in clinical tumor therapy as one of the main strategies of immunotherapy. However, the traditional cancer vaccine for a single antigen has a low benefit rate due to the individual differences in patients. Here, we report a R837-loaded poly(lactic-co-glycolic acid) nanovaccine coated with a calcinetin (CRT)-expressed cancer cell membrane antigen for immunotherapy. The cell membrane antigen that possessed a complete antigen array was obtained by inducing immunogenic cell death in vitro, avoiding the severe systemic toxicity of chemotherapy in vivo. The nanovaccine codelivers the adjuvant R837 and the Luc-4T1 membrane antigen, triggering a personalized immune response to the corresponding tumor. Moreover, the calcinetin exposed on the surface of the nanovaccine induces the active uptake of dendritic cells, consequently enhancing the antitumor effect. Meanwhile, the nanovaccine activates immune memory cells to provide long-term protection. Our work provides a new strategy for a clinical personalized antitumor vaccine.

Autophagy is involved in the occurrence and development of tumors. Here, a pH-responsive polymersome codelivering hydroxychloroquine (HCQ) and tunicamycin (Tuni) drugs is developed to simultaneously induce endoplasmic reticulum (ER) stress and autophagic flux blockade for achieving an antitumor effect and inhibiting tumor metastasis. The pH response of poly(β-amino ester) and HCQ synergistically deacidifies the lysosomes, thereby blocking the fusion of autophagosomes and lysosomes and lastly blocking autophagic flux. The function mechanism of regulating autophagy was systematically investigated on orthotopic luciferase gene–transfected, 4T1 tumor–bearing BALB/c mice through Western blot and immunohistochemistry analyses. The Tuni triggers ER stress to regulate the PERK/Akt signaling pathway to increase the autophagic level. The “autophagic stress” generated by triggering ER stress–induced autophagy and blocking autophagic flux is effective against tumors. The reduced expression of matrix metalloproteinase-2 due to ER stress and reduced focal adhesions turnover due to the blockade of autophagic flux synergistically inhibit tumor metastasis.