Background and Objectives: Aggressive cancer development is characterized by rapid tumor growth and progressive immune dysfunction. Tumor-derived microRNAs (miRNAs) emerge as master regulators of both malignant transformation and immune evasion, making them promising therapeutic targets. Using the highly aggressive CT-26 peritoneal adenomatosis model, this study explored the potential of selective miRNA inhibition to simultaneously suppress tumor growth and overcome immunosuppression. Methods and Results: Our results revealed that inhibition of miR-155, miR-21, and miR-17 by methylsulfonyl phosphoramidate (mesyl) oligonucleotides exhibited markedly different therapeutic profiles. miR-155 inhibition demonstrated minimal efficacy. miR-21 suppression provided early tumor regression and prevented cancer-associated thymic atrophy, translating into extended survival. miR-17 inhibition displayed delayed but superior tumor growth inhibition, significantly reducing pathologically elevated polymorphonuclear myeloid-derived suppressor cell (MDSC) populations, and nearly doubled animal lifespan. Combination therapy targeting all three miRNAs integrated these complementary mechanisms, maintaining consistent anti-tumor efficacy across early and late stages while providing thymic protection and MDSC reduction. Importantly, therapeutic responses in vivo substantially exceeded predictions based on in vitro tumor cell proliferation and motility measurements, revealing critical contributions of systemic immunomodulation. Conclusions: These findings demonstrate that miRNA inhibition reshapes tumor–immune interactions, positioning anti-miRNA therapeutics as immunomodulatory agents for effective colorectal cancer treatment.

Occupational chronic obstructive pulmonary disease (O-COPD) represents a lung disorder attributable to occupational exposures that are characterized by early development of airway remodeling and pulmonary fibrosis. O-COPD is poorly recapitulated by existing preclinical models. This study aimed to perform comparative characterization of an O-COPD patient cohort exposed to industrial aerosols and to develop a relevant murine model that accurately mirrors the human pathology. In the patient cohort, it was shown that the O-COPD phenotype is associated with the chemical composition of industrial aerosols and mediated by a specific inflammatory pattern with predominant obstructive changes and increased bronchial reactivity upon exposure to metal particles, as well as irreversible fibrotic changes in the lungs upon exposure to silicon dioxide. In the murine model, silica nanoparticles (SiNPs) or magnetic nanoparticles (MNPs) were utilized. Repeated intranasal SiNP administrations have been shown to reflect one of the main features of O-COPD—progressive airway remodeling and fibrosis, observed even after elimination of SiNPs. Administration of MNPs in the same regimen did not result in fibrotic changes in the lungs, partially recapitulating the human pathology resulting from exposure to the complex composition of industrial aerosols as well as the specific properties of chemically synthesized nanoparticles. Thus, the integrative data from the human cohort and animal model provides a reflective platform to advance the investigation of O-COPD mechanisms and development of interventions for fibrotic lung pathology.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that strongly suppress immunity and expand during tumor progression. Various antitumor chemotherapy agents can induce MDSC accumulation, reducing treatment effectiveness. We investigated the impact of the CHOP regimen and its components (cyclophosphamide (CTX), doxorubicin, vincristine, and prednisolone) on the dynamics of MDSC accumulation and the associated changes in immune cell profiles in the peripheral blood and spleen of healthy and lymphosarcoma RLS₄₀-bearing CBA mice. CHOP induced significant thymic atrophy and splenomegaly, T-cell depletion, and robust accumulation of MDSCs, primarily polymorphonuclear MDSCs. Kinetic analysis in healthy mice revealed splenic MDSC expansion and T-cell depletion peaked 10-day post-CHOP, driven mainly by CTX; whereas doxorubicin, vincristine, and prednisolone exerted minimal immunological effects. To mitigate CTX-induced MDSCs, glycyrrhizic acid (GLZ), a natural triterpenoid with known immunomodulatory properties, and febroxolone methyl (FM), its novel cyano enone derivative, were administered to CTX-treated mice. GLZ significantly attenuated splenic MDSC accumulation, partially restored T-cell function, and improved immune organ morphology. Conversely, FM exacerbated immunosuppression by expanding MDSCs, enhancing their function by upregulation of Nos1 and Ido1 in vivo, and promoting the generation of highly immunosuppressive bone marrow-derived MDSCs in vitro. Thus, our results highlight CTX’s central role in CHOP-induced MDSC expansion. The structure-dependent duality of triterpenoids, countering (GLZ) or promoting (FM) MDSC expansion, offers therapeutic potential for pathologies ranging from chemotherapy-induced side effects to autoimmunity.