Durable Attenuation of Tumor pH–Platelet Linkage Reinstates Bioorthogonal Targeting of Residual Tumors Post-Debulking

There are circumstances where tumors can only be partially resected. Therefore, multimodality therapy targeting post-operative residuals is important. Here, we show that bioorthogonal click chemistry enables targeted delivery to heterogeneous tumors, but its utility against tumor post-debulking is ineffective due to platelet cloaks that shield tumor cells from bioorthogonal pairing. We further discover tumor-infiltrating platelet levels respond to local pH changes. Elucidating this pH-platelet linkage, we design an injectable hydrogel for resection cavity implantation that simultaneously azido-tags tumor cells and inhibit their catalysis to acidify surrounding milieu. Unlike transient buffering, tumor acidification blockade sustains pH normalization, leading to durable platelet reduction. This reinstates bioorthogonal targeting of dibenzyl cyclooctyne-modified nanoparticles, thereby enhancing photodynamic ablation of residuals while amplifying systemic antitumor immunity. Concurrently, platelet/pH normalization interrupts metastasis cascade from invasion to circulation to colonization. Overall, attenuating tumor pH-platelet linkage unlocks bioorthogonal chemistry as a potential option for adjuvant therapy after tumor debulking.