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Chemotherapy remains a major therapeutic approach to cancer treatment. However, its effectiveness can be compromised by the heterogeneity of a solid tumor, in which different cancer cell populations display varied responses to chemotherapy. Such an intratumor heterogeneous structure is maintained by the cancer stem-like cells (CSCs) with inherent capacities for self-renewal and differentiation, giving rise to diverse cell populations. To address this, we proposed a combinational strategy in which tumor lesion-targeted Notch signaling regulation was achieved to disrupt CSC-mediated cancer heterogeneity, thereby sensitizing solid tumors toward paclitaxel (PTX). Specifically, gamma-secretase inhibitor LY-411,575 was co-delivered with PTX using a near-infrared (NIR) light-controlled drug delivery system to realize targeted ablation of both differentiated cancer cells and undifferentiated CSCs. By enabling precise regulation of the Notch pathway at the tumor site through NIR light, we observed significantly elevated efficacy of chemotherapy and notable prevention of postsurgical tumor relapse while minimizing systemic side effects. The devised strategy shows promise in addressing the nonspecific inhibition of stemness across various organs, a challenge that hampers the clinical translation of gamma-secretase inhibitors in cancer therapy.

The histone locus body (HLB) is a membraneless organelle that determines the transcription of replication-dependent histones. However, the mechanisms underlying the appropriate formation of the HLB in the nucleus but not in the cytoplasm remain unknown. HLB formation is dependent on the scaffold protein NPAT. We identify KPNA3 as a specific importin that drives the nuclear import of NPAT by binding to the nuclear localization signal (NLS) sequence. NPAT undergoes phase separation, which is inhibited by KPNA3-mediated impairment of self-association. In this, a C-terminal self-interaction facilitator (C-SIF) motif, proximal to the NLS, binds the middle 431-1,030 sequence to mediate the self-association of NPAT. Mechanistically, the anchoring of KPNA3 to the NPAT-NLS sterically blocks C-SIF motif-dependent NPAT self-association. This leads to the suppression of aberrant NPAT condensation in the cytoplasm. Collectively, our study reveals a previously unappreciated role of KPNA3 in modulating HLB formation and delineates a steric hindrance mechanism that prevents inappropriate cytoplasmic NPAT condensation., (© 2024 Xu et al.)