Novel NK cell-like phenotype expressing CCR5 and its ligands elicits tumor-specific acquired immunity to carcinomatous peritonitis via host NK-derived IFN-γ

Background: Natural killer (NK) cell-based immunotherapies remain largely ineffective against solid tumors and strategies that directly enhance NK cell cytotoxicity often fail to establish durable tumor control. To address this limitation, we developed GAIA-102, a novel NK-like phenotype with enhanced tumor-homing capacity, and its scalable derivative, expanded GAIA-102 (exp_GAIA). Here, we evaluated whether exp_GAIA can engage host immunity to drive durable response. Methods: A syngeneic lethal murine model of carcinomatous peritonitis was used to assess exp_GAIA. Following adoptive transfer of exp_GAIA with recombinant human interleukin-2 (rhIL-2), antitumor efficacy, survival and immune response were evaluated. Mechanistic studies quantified chemokine production and examined CCR5-dependent recruitment and expansion of endogenous NK cells, interferon-γ (IFN-γ) secretion, and activation of tumor-specific CD8+T cells. Tumor immunogenic cell death (ICD) was assessed by calreticulin (CRT) surface translocation and analyzed for its association with endogenous NK expansion. Results: Treatment with exp_GAIA plus rhIL-2 induced complete tumor regression and generated durable, tumor-specific adaptive immune response that required CD8+T cells. Mechanistically, exp_GAIA secreted CCR5-binding chemokines, particularly CCL3, thereby recruiting endogenous NK cells into tumor. Endogenous NK cells produced IFN-γ, which activated tumor-specific CD8+T cells and established an innate-to-adaptive cytotoxicity axis. In parallel, exp_GAIA triggered tumor ICD characterized by CRT translocation, which further promoted in situ expansion of endogenous NK cells. Conclusions: In combination with rhIL-2, exp_GAIA integrates endogenous NK activity with induction of long-lasting, CD8+T cell-dependent antitumor immunity via a CCR5-CCL3-NK-IFN-γ-CD8 pathway, reinforced ICD with CRT exposure. These findings support exp_GAIA+rhIL-2 as a new NK-based strategy for durable control of solid tumors.