Reversing tumor fibrosis for potentiating chemo-immunotherapy via lactic acid exhaustion by codelivery of bicarbonate and JQ1

Abstract

Tumor fibrosis imposes a formidable barrier against effective chemo-immunotherapy, typically resulting in limited infiltration of immune cells and poor drug penetration into the tumor. In this study, it was revealed that intratumoral lactic acid exhaustion can relieve tumor fibrosis by suppressing TGF-β pathway. The bicarbonate liposomes loaded with JQ1 (JQ1/NaHCO₃@TLip) was constructed, with surface modification with lactoferrin (LF) that enabled tumor-targeting delivery via binding with LRP-1 receptors. Intratumoral lactic acid can be reduced via both neutralization and epigenetic-metabolism regulation. JQ1/NaHCO₃@TLip was demonstrated to effectively reverse tumor fibrosis, thereby promoting immune cell infiltration, and enhancing deep penetration of both nanomedicine (e.g., liposomal doxorubicin (DOX@Lip)) and protein drugs (e.g., anti-PD-1). Importantly, the combination of low-dose DOX@Lip and JQ1/NaHCO₃@TLip exhibited remarkable efficacy with reducing side toxicity. This combination approach also effectively inhibited tumor recurrence and distant metastasis. Moreover, pretreatment with JQ1/NaHCO₃@TLip showed a synergistic effect on enhancing tumor inhibition efficacy of anti-PD-1 therapy. These findings indicate that JQ1/NaHCO₃@TLip is promising as a nano-adjuvant to enhance chemo-immunotherapy via lactic acid exhaustion.