Inhalable Cryo-Shocked Tumor Cells for Synergistic Chemoimmunotherapy

Lung cancer, particularly nonsmall cell lung cancer (NSCLC), poses significant therapeutic challenges due to frequent late-stage diagnosis and limited treatment efficacy. While chemoimmunotherapy has emerged as a promising approach, its clinical application is hampered by systemic toxicity and pharmacokinetic asynchrony. To address these limitations, we developed an innovative inhalable platform utilizing liquid nitrogen-treated tumor cells (LNT cells) that serve dual functions as both drug carriers and potent immunostimulators. These LNT cells retain their structural integrity while being rendered nonviable, exposing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) that robustly promote dendritic cell (DC) maturation and proinflammatory cytokine secretion via activation of Toll-like receptor (TLR) and nuclear factor kappa B (NF-κB) signaling pathways. This biomimetic system demonstrates excellent pulmonary retention following inhalation and exhibits high drug-loading capacity, with the preserved cellular architecture of LNT cells enabling the sustained release of doxorubicin (DOX) under physiologically relevant conditions. The resulting LNT-DOX formulation combines controlled chemotherapeutic delivery with immunogenic cell death (ICD) induction, achieving synergistic therapeutic effects. In both orthotopic lung cancer and aggressive pulmonary metastasis models, inhalation of LNT-DOX demonstrated superior tumor suppression, significantly prolonged survival, and reduced systemic toxicity compared with conventional DOX administration. Mechanistic studies revealed that this enhanced efficacy stems from a multifaceted immunomodulatory response, including sustained local chemotherapy, robust DC activation, M1 macrophage polarization, and significant recruitment of NK cells and CD8⁺ T cells into the tumor microenvironment. Our findings present a transformative approach to lung cancer treatment that simultaneously delivers targeted chemotherapy and in situ immune activation through an inhalable, tumor cell-based platform.