<p>The inevitable splenic sequestration of nanomedicine represents a major delivery challenge that compromises tumor accumulation and may contribute to off-target burden. Rather than attempting to eliminate this fate, we propose to functionally repurpose it into an immunologically productive process. Distinct from conventional spleen-targeted strategies, we aimed to modulate the biological fate of tumor-targeted nanomedicines by engineering their surface with screening-selected hybrid cell membranes. A tumor cell membrane-to-erythrocyte membrane ratio of 10:1(TRM) was identified as a representative balance point that preserves optimal tumor-associated accumulation while biasing a fraction of off-target nanoparticles (NPs) toward the spleen. Zinc imidazolate framework-8 (ZIF-8) NPs were employed as a model therapeutic core. The resulting hybrid cell membrane–camouflaged nanoplatform (TRM@ZIF-8) exhibited immune-associated effects, where the tumor-associated fraction was linked to inflammasome-related signaling and inflammatory cell death–associated responses, while the spleen-biased fraction was associated with activation of splenic antigen-presenting cells. This behavior is consistent with the collective influence of membrane-associated protein features, including functions related to cluster of differentiation 47(CD47) and Band 3, together with the intrinsic immunostimulatory properties of the ZIF-8 core. Importantly, splenectomy markedly attenuated the therapeutic effect, providing organ-level evidence that spleen involvement is functionally associated with the observed antitumor immune response and tumor growth suppression. This work provides a proof-of-concept framework for guiding off-targeted nanomedicine repurposing in spleen for cancer immunotherapy, rather than regarding it solely as a delivery limitation.</p> Graphical Abstract <p></p>