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Lung metastasis remains a major clinical challenge, often associated with poor prognosis due to its highly immunosuppressive microenvironment and fibrosis-induced complications. Current treatment strategies, including chemotherapy, radiotherapy, and immunotherapy, have shown limited efficacy in addressing lung metastases, and less attention has been given to their associated fibrosis. Here, we develop a ‘cell-in-cell’ delivery platform (i.e., lyophilized bacteria-infected tumor cells (LyoBT)) to simultaneously target lung metastasis and their associated fibrosis. This approach leverages the intrinsic lung tropism of tumor cells and the immunostimulatory properties of both tumor cells and bacteria, while mitigating tumorigenic and pathogenic risks through lyophilization. Notably, bacterial infection led to phenotypic changes in tumor cells. Specifically, characterization of LyoBT revealed upregulated expression of CD47, CD44, and E-cadherin, further enhancing lung targeting. Furthermore, increased calreticulin (CRT) exposure in LyoBT coupled with bacterial immune-stimulatory properties, promoted anti-tumor immunity. In a melanoma lung metastasis model, LyoBT demonstrated efficient accumulation in the lungs, leading to robust anti-tumor immune activation and significant inhibition of tumor progression. Notably, LyoBT also reduced fibrosis-associated immune cell infiltration and cytokine release, alleviating lung metastasis-induced fibrosis. Furthermore, LyoBT served as a drug delivery platform for immune checkpoint inhibitors (aPD-L1), with LyoBT@aPD-L1 demonstrating enhanced therapeutic efficacy. Our findings highlight the potential of LyoBT as a dual-functional strategy to combat both lung metastases and their associated fibrosis, offering a promising new avenue for bacterial-based cancer immunotherapy. The lyophilized bacteria-infected tumor cells, a cell-in-cell platform, exhibited enhanced lung accumulation, promoted immunogenicity, and improved biosafety for treating lung metastases and associated fibrosis. These benefits were observed when the platform was used either i) alone or ii) in combination with immune checkpoint blockades delivered by the platform, with the latter further enhancing treatment efficacy. [Display omitted] •Lyophilized tumor cells serve as a safe and efficient delivery platform for bacteria.•Lyophilization eliminates biosafety risks while preserving immunomodulatory properties.•LyoBT leads to dual inhibition of lung metastasis and associated fibrosis.•LyoBT serves as a versatile drug delivery vehicle for combination therapies.

Owing to its unique mechanism of abundant pathogen-associated molecular patterns in antitumor immune responses, bacteria-based cancer immunotherapy has recently attracted wide attention. Compared to traditional cancer treatments such as surgery, chemotherapy, radiotherapy, and phototherapy, bacteria-based cancer immunotherapy exhibits the versatile capabilities for suppressing cancer thanks to its preferentially accumulating and proliferating within tumors. In particular, bacteria have demonstrated their anticancer effect through the toxins, and other active components from the cell membrane, cell wall, and dormant spores. More importantly, the design of engineering bacteria with detoxification and specificity is essential for the efficacy of bacteria-based cancer therapeutics. Meanwhile, bacteria can deliver the cytokines, antibody, and other anticancer theranostic nanoparticles to tumor microenvironments by regulating the expression of the bacterial genes or chemical and physical loading. In this review, we illustrate that naïve bacteria and their components can serve as robust theranostic agents for cancer eradication. In addition, we summarize the recent advances in efficient antitumor treatments by genetically engineering bacteria and bacteria-based nanoparticles. Further, possible future perspectives in bacteria-based cancer immunotherapy are also inspected.

Cytokine treatment provides clinical benefits by stimulating the patient’s immune system to attack cancer cells. However, its effectiveness as a monotherapy is limited because of its systemic toxicity and short in vivo half-life. To address these limitations, we assessed the therapeutic impact of delivering cytokines specifically to tumors using tumor-targeting bacteria. A Salmonella strain was engineered to minimize its pathogenic traits by deleting key elements ( Salmonella pathogenicity islands-1 and -2) responsible for invasion and replication within the mammalian host, generating the ΔSPI-1ΔSPI-2 strain. A plasmid encoding a synthetic type 3 secretion system (SynT3SS V3.0) was introduced into this strain using a previously reported genetic system after reorganizing the gene clusters and placed under control of the P tet promoter. Finally, the anticancer cytokine Neoleukin-2/15 (Neo-2/15) was introduced into the strain via a separate plasmid. This plasmid encoded an N-terminal secretion signal from SptP (SptP 167 ) and was driven by the constitutive promoter P J23110 . Upon inducing SynT3SS V3.0 using doxycycline, the recombinant protein SptP 167 ::Neo-2/15 was secreted into the bacterial culture supernatant with a yield of 0.37 ± 0.07 mg/L. Starved cytotoxic T lymphocytes treated with the culture supernatant containing SptP 167 ::Neo-2/15 proliferated, as observed with hIL-2, purified Neo-2/15, or purified SptP 167 ::Neo-2/15 treatment. Administering Salmonella ΔSPI-1ΔSPI-2 strains carrying plasmids encoding SynT3SS V3.0 and SptP 167 ::Neo-2/15 caused tumor regression and lifespan extension in CT26 tumor-bearing mice. Engineered bacteria represent a promising new modality for cancer therapy by combining the targeted delivery of therapeutic cytokines with the synergistic immunostimulatory effects of bacterial intrinsic factors. Furthermore, this strategy could be adapted for other protein-based payloads, potentially enabling the tumor-specific delivery of a diverse range of therapeutic agents.

Traditional chemotherapy, a prevalent cancer treatment modality, is associated with significant side effects and often leads to treatment failure. Non-specific drug distribution and chemoresistance are the main factors contributing to this failure. Certain distinctive characteristics of the tumor microenvironment (TME), including hypoxia, acidic pH, and increased interstitial fluid pressure, render cancer cells resistant to conventional treatments. Multiple approaches have been devised to enhance the treatment efficiency of neoplasms and overcome chemoresistance. Nowadays, bacteria-based cancer therapy has garnered significant interest in both preclinical and clinical research, owing to its distinctive mechanism and various applications in eliciting host antitumor immunity. Due to their inherent tumor tropism, elevated motility, and capacity for quick colonization in the conducive TME, bacteria are increasingly being considered for targeted tumor treatment. Bacteria, rich in pathogen-associated molecular patterns (PAMPs), can efficiently stimulate immune cells even inside the immunosuppressive TME, boosting the particular immune detection and eradication of tumor cells. Furthermore, outer membrane vesicles (OMVs), cytoplasmic membrane vesicles (CMVs), and their derived physiological components exhibit analogous functionalities to their parental cells. This review article is representative of the latest innovations in bacteria-based immunosuppressive TME reprogramming. Additionally, the article discusses future directions in this research area, drawing on current advances. Graphical abstract Highlights Salmonella enhances the activity of CTLs and NK cells while reducing Tregs populations within the TME, thereby promoting antitumor immune responses. Listeria infects suppressive myeloid cells, boosting IL-12 and antitumor immunity. Engineered bacteria selectively colonize tumors and deliver immunostimulatory agents, reprogramming the TME to enhance antitumor immunity. Engineered OMVs act as targeted nanocarriers, accumulating in tumors and activating immune responses through PAMP delivery. Bacteria-based therapy exploits tumor hypoxia, overcoming chemo- and radio resistance.

Microbes have an immense metabolic capability and can adapt to a wide variety of environments; as a result, they share complicated relationships with cancer. The goal of microbial-based cancer therapy is to treat patients with cancers that are not easily treatable, by using tumor-specific infectious microorganisms. Nevertheless, a number of difficulties have been encountered as a result of the harmful effects of chemotherapy, radiotherapy, and alternative cancer therapies, such as the toxicity to non-cancerous cells, the inability of medicines to penetrate deep tumor tissue, and the ongoing problem of rising drug resistance in tumor cells. Due to these difficulties, there is now a larger need for designing alternative strategies that are more effective and selective when targeting tumor cells. The fight against cancer has advanced significantly owing to cancer immunotherapy. The researchers have greatly benefited from their understanding of tumor-invading immune cells as well as the immune responses that are specifically targeted against cancer. Application of bacterial and viral cancer therapeutics offers promising potential to be employed as cancer treatments among immunotherapies. As a novel therapeutic strategy, microbial targeting of tumors has been created to address the persisting hurdles of cancer treatment. This review outlines the mechanisms by which both bacteria and viruses target and inhibit the proliferation of tumor cells. Their ongoing clinical trials and possible modifications that can be made in the future have also been addressed in the following sections. These microbial-based cancer medicines have the ability to suppress cancer that builds up and multiplies in the tumor microenvironment and triggers antitumor immune responses, in contrast to other cancer medications. Graphical abstract