Nanodrugs Incorporating LDHA siRNA Inhibit M2-like Polarization of TAMs and Amplify Autophagy to Assist Oxaliplatin Chemotherapy against Colorectal Cancer

Abstract

Oxaliplatin (OXA) is a first-line chemotherapeutic agent for treating colorectal cancer (CC). However, the chemotherapeutic effect of OXA on CC is limited by the M2-like polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) and protective autophagy of tumor cells. Here, a cationic polymer APEG-PAsp(PEI) (PAPEI) was prepared to deliver smallinterfering RNA (siRNA) to silence the lactate dehydrogenase A (LDHA) gene (LDHA-siRNA) to enhance the chemotherapeutic effect of OXA on CC. The PAPEI/LDHA-siRNA nanocomplex effectively silenced the LDHA gene to inhibit the secretion of lactic acid from tumor cells, resulting in inhibition of the M2-like polarization of TAMs. In addition, the nanocomplex also amplified OXA-induced autophagy and transformed protective autophagy into autophagic death. Consequently, the combination treatment of OXA and PAPEI/LDHA-siRNA showed a dramatically increased chemotherapeutic effect on CC compared with the OXA-alone treatment, which also suggested its attractive potential for treating CC-like immune "cold" tumors.

CircHIF1A induces cetuximab resistance in colorectal cancer by promoting HIF1α-mediated glycometabolism alteration

“…In addition, the level of LDHA is related to chemotherapy sensitivity [ 47 ]. Inhibiting LDHA can reduce the resistance of CRC cells to 5-FU [ 48 ] and Oxaliplatin [ 49 ]. In this study, the expression levels of GLUT1, LDHA, PFKFB3, PKM2 and HK2 were elevated in Cetuximab resistant cells, and downregulating circHIF1A reduced the promoter activity and expression of GLUT1 and LDHA, suggesting that the increased level of glycometabolism, especially glycolysis, in Cetuximab resistant CRC cells is closely related to the intracellular high level of circHIF1A.…”

Nanomaterials-Involved Tumor-Associated Macrophages’ Reprogramming for Antitumor Therapy

“…Now that lactate dehydrogenase A (LDHA) as a key enzyme in converting pyruvate into lactic acid can regulate TAMs into M1 phenotype, 152 effectively reduce lactate production and suppress TMAs' M2 polarization. 153 Therefore, TAMs were accurately reeducated into M1 phenotype. In addition to using natural or simulated enzymes to downregulate lactate, Zhang and co-workers constructed a bacteria-based nanomaterial (Bac@RFH) as bioconsumer to persistently consume lactate for TAMs' programming and enhanced immunotherapy.…”

“…With the sustained lactate consumption and acidity reduction, TAMs were repolarized from M2 toward M1 subtype (Figure a). Now that lactate dehydrogenase A (LDHA) as a key enzyme in converting pyruvate into lactic acid can regulate TAMs into M1 phenotype, Hu et al prepared a nanocomplex to deliver silencing LDHA genes containing siRNA (LDHA-siRNA) to effectively reduce lactate production and suppress TMAs’ M2 polarization . Moreover, since lactate oxidase (LOx) is another enzyme to deplete lactate, Li et al encapsulated LOx and SIRPα silencing genome-editing plasmids in the zeolitic imidazolate framework (ZIF)-67 (LPZ) to relieve hypoxic TME and reprogram TAMs (Figure b–d) .…”

Intelligent Delivery Systems in Tumor Metabolism Regulation: Exploring the Path Ahead

“…This immunity‐enhancing, metabolism‐targeting strategy‐based combination therapy demonstrated potent starvation‐killing effects and anti‐tumor immune response. Using siRNA knockdown of LDHA [ 96 ] or MCT4 [ 97 ] was shown to significantly induce M2‐polarized macrophages to shift to an anti‐tumor phenotype by reducing environmental lactate concentration. Studies indicate that by downregulating LDHA, it's possible to inhibit the production of granulocyte‐colony stimulating factor and granulocyte‐macrophage colony‐stimulating factor, thereby restraining the recruitment of myeloid‐derived suppressor cells and enhancing anti‐tumor immunity.…”