Targeting LAMP2 synergizes with gemcitabine to inhibit bladder cancer progression via modulating STING degradation and regulating macrophage phenotypes.

Bladder cancer (BLCA) is an aggressive malignancy characterized by metastasis and drug resistance, creating an urgent demand for novel therapeutic targets. The lysosomal protein LAMP2 acts as a key oncogenic driver in BLCA and modulates the degradation of STING. As reported in prior studies, mechanistically, p62-mediated macroautophagy and HSC70-dependent chaperone-mediated autophagy (CMA) facilitate STING degradation. LAMP2 increases STING ubiquitination, leading to its lysosomal degradation in BLCA. Moreover, LAMP2 knockdown suppresses BLCA cell proliferation and migration. In our experimental systems, it also induces M1-type tumor-associated macrophages (TAMs) polarization and reduces TAM infiltration. RNF5 and TRIM56 are known to mediate K48/K63-linked ubiquitination of STING. Here, we demonstrate LAMP2 modulates this ubiquitination pattern in BLCA. Via virtual screening, we discover MRGPRX4 modulator-2 (Mm-2), a LAMP2-binding small molecule with anti-tumor activity against BLCA. Combined with gemcitabine (GEM), Mm-2 blocks autophagic flux and activates STING signaling. It also alters TAM phenotypes in our in vitro and in vivo models. The LAMP2-STING-TAMs axis shows potential as a therapeutic target for modulating the tumor immune microenvironment (TME) and affecting drug response in BLCA.