The presence of anti-polyethylene glycol (PEG) antibodies significantly impacts the clinical translation and therapeutic efficacy of PEGylated liposomes. Current research on anti-PEG antibodies primarily focuses on strategies to reduce their production. However, the growing prevalence of anti-PEG antibody-positive individuals has become an undeniable challenge. To address this issue, we have designed an asymmetrical branched PEG lipid derivative (PEG2,5K-DSPE) aimed at minimizing the binding of anti-PEG antibodies. We have further prepared 1,1’-dioctadecyl-3,3,3,3’-tetramethylindodicarbocyanine iodide (DiR) liposomes (P2,5K-DiR) and mitomycin C lipid prodrug (MSC) liposomes (P2,5K-MSC) modified with this derivative. Classic PEG2000 lipid derivatives, after binding to anti-PEG IgG, are not only cleared by the liver but can also be taken up by tumor-associated macrophages in the tumor stroma, leading to reduced anti-tumor efficacy. Notably, the PEG2,5K-DSPE can form a bilayer structure on the surface of liposomes, which reduces the recognition and binding of anti-PEG IgG antibody. This modification enhances DiR liposomes and MSC liposomes accumulation in tumor tissues and promotes cancer-immune circulation. As a result, these liposomes significantly improve the effectiveness of photothermal therapy and chemotherapy in cancer treatment. Overall, our study provides a new strategy for the clinical application of PEGylated liposomes in anti-PEG antibody-positive populations.