Non-Hodgkin lymphomas (NHL) are the most frequent hemato-oncological malignancies. Despite recent major advances in treatment, a substantial proportion of patients relapses highlighting the need for new therapeutic modalities. Promissory results obtained in pre-clinical studies are usually not translated when moving into clinical trials. Pre-clinical studies are mainly conducted in animals with high tumor burden; instead patients undergo chemotherapy as first line of treatment and most likely are under remission when immunotherapies are applied. Thus, an animal model that more closely resembles patients’ conditions would be a valuable tool. BALB/c mice were injected subcutaneously with A20 lymphoma cells and after tumor development different doses of chemotherapy were assessed to find optimal conditions for minimal residual disease (MRD) establishment. Tumor growth and survival, as well as drugs side effects, were all evaluated. Complete lymphoma remission was monitored in vivo using positron emission tomography (PET), and the results were correlated with histology. Immunological status was assessed by splenocytes proliferation assays in NHL-complete remission mice and by analyzing tumor cell infiltrates and chemokines/cytokines gene expression in the tumor microenvironment of animals with residual lymphoma. Two cycles of CHOP chemotherapy at days 25 and 35 post-tumor implantation induced complete remission for around 20 days. PET showed to be a suitable follow-up technique for MRD condition with 85.7 and 75% of sensibility and specificity respectively. Proliferative responses upon mitogen stimulation were similar in animals that received chemotherapy and wild type mice. Tumors from animals with residual lymphoma showed higher numbers of CD4+ and CD8+ and similar numbers of NK, neutrophils and Tregs infiltrating cells as compared with non-treated animals. Gene expression of several cytokines as well as an array of chemokines associated with migration of activated T cells to tumor sites was upregulated in the tumor microenvironment of animals that received chemotherapy treatment. We established a NHL-B pre-clinical model using standard chemotherapy to achieve MRD in immunocompetent animals. The MRD condition is maintained for approximately 20 days providing a therapeutic window of time where new immunotherapies can be tested in conditions closer to the clinics.

Localized melanoma is easy to remove by surgery, resulting in a high five-year relative survival rate. However, when disseminated the disease management is challenging. The use of immunotherapies, such as anti-checkpoint monoclonal antibodies, has improved treatment options but still only a small percentage of patients responds to these expensive treatments. In this work, we apply a bacteria-based immunotherapy using LVR01, an attenuated Salmonella enterica serovar Typhimurium, as neoadjuvant therapy one week before surgery in a preclinical disseminated murine melanoma model. LVR01 administration resulted in tumor growth retardation prior to tumor resection, due to a rapid upregulation of inflammatory genes in the tumor microenvironment. As a consequence, cell infiltration increased, particularly neutrophils, macrophages and NK cells, being the latter involved in Salmonella anti-tumor activity. Besides, tumor-draining lymph node infiltration is characterized by reinvigorated CD4⁺ and CD8⁺ lymphocytes. Induced immune response could account for the prevention or delay of tumor recurrence and appearance of metastasis, resulting in a prolonged overall survival after surgery. Furthermore, upon rechallenge mice show partial protection, suggesting the existence of specific memory against melanoma. We propose that neoadjuvant LVR01 treatment could represent an interesting inexpensive alternative that may ease tumor resection, while preventing tumor recurrence in patients with melanoma.

Bacteria-based cancer immunotherapies are regaining attention due to recent advances in understanding the mechanisms underlying their efficacy, making them promising tools for cancer treatment. Among these, Salmonella stands out as one of the most extensively studied microorganisms in this field. Its ability to directly induce tumor cell death while stimulating the immune system offers unique therapeutic advantages, as cell death within an inflammatory environment may enhance the release of tumor antigens and promote effective antitumor immune responses. Although multiple studies have addressed Salmonella-induced cell death, the nomenclature and classification of death modalities are often inconsistent—either because earlier reports predate the formalization of certain death pathways, or due to overlapping criteria between different types of cell death. This review aims to comprehensively analyze the available evidence on Salmonella-induced apoptosis, pyroptosis and autophagy, as well as other less characterized death modalities. Given that most mechanistics evidence on Salmonella-induced cell death has been generated in myeloid cells, we primarily focus on the myeloid compartment while integrating available observations from tumor cells and other immune populations when relevant, organizing the existing data under current definitions and concepts, and highlighting the challenges of manipulating these pathways to optimize bacterial-based immunotherapies.

Attenuated engineered strains of Salmonella have emerged as promising tools in cancer immunotherapy due to their intrinsic tumor-targeting properties and their ability to reshape the tumor immune microenvironment. Beyond their direct cytotoxic effects on tumor cells , Salmonella profoundly modulates both innate and adaptive immune responses, impacting multiple steps of the cancer–immunity cycle. In this review, we discuss how attenuated Salmonella induces immunogenic tumor cell death, promotes antigen release and cross-presentation, enhances lymphocyte activation, and facilitates immune cell infiltration into the tumor microenvironment. We also address its role in controlling metastatic disease and the induction of long-term adaptive immune memory. Furthermore, we highlight unresolved questions regarding the contribution of immune activation, tolerance, and trained immunity, which may underlie the transient nature of antitumor effects observed in some models. Finally, we examine the translational hurdles that have limited clinical efficacy—such as the balance between attenuation and potency, endotoxin tolerance, and preexisting immunity—and outline emerging engineering strategies to overcome them. Understanding these mechanisms is essential for optimizing Salmonella -based strategies and their integration with current immunotherapies.