Growing literature has documented varying toxic potencies of source- or site-specific fine particulate matter (PM2.5), as opposed to the practice that treats particle toxicities as independent of composition given the incomplete understanding of the toxicity of the constituents. Quantifying component-specific contribution is the key to unlocking the geographical disparities of particle toxicity from a mixture perspective. In this study, we performed integrated mixture toxicity experiments and modeling to quantify the contribution of metals and polycyclic aromatic hydrocarbons (PAHs), two default culprit component groups of PM2.5 toxicity, to in vitro oxidative stress caused by wintertime PM2.5 from Beijing and Guangzhou, two megacities in China. PM2.5 from Beijing exhibited greater toxic potencies at equal mass concentrations. The targeted chemical analysis revealed higher burden of metals and PAHs per unit mass of PM2.5 in Beijing. These chemicals together explained 38 and 24% on average of PM2.5-induced reactive oxygen species in Beijing and Guangzhou, respectively, while >60% of the effects remained to be resolved in terms of contributing chemicals. PAHs contributed approximately twice the share of the PM2.5 mixture effects as metals. Fe, Cu, and Mn were the dominant metals, constituting >80% of the metal-shared proportion of the PM2.5 effects. Dibenzo[a,l]pyrene alone explained >65% of the PAH-shared proportion of the PM2.5 toxicity effects. The significant contribution from coal combustion and vehicular emissions in Beijing suggested the major source disparities of toxicologically active PAHs between the two cities. Our study provided novel quantitative insights into the role of varying toxic component profiles in shaping the differential toxic potencies of city-specific PM2.5 pollution.