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 (expGAIA). Here, we evaluated whether expGAIA can engage host immunity to drive durable response. Methods A syngeneic lethal murine model of carcinomatous peritonitis was used to assess expGAIA. Following adoptive transfer of expGAIA 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 expGAIA plus rhIL-2 induced complete tumor regression and generated durable, tumor-specific adaptive immune response that required CD8 + T cells. Mechanistically, expGAIA 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, expGAIA triggered tumor ICD characterized by CRT translocation, which further promoted in situ expansion of endogenous NK cells. Conclusions In combination with rhIL-2, expGAIA 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 expGAIA+rhIL-2 as a new NK-based strategy for durable control of solid tumors.
Zheng et al. (Wed,) studied this question.