A series of vanadium and phosphorus heteronuclear oxide cluster cations (V_xP_yO_z⁺) are prepared by laser ablation and the reactions of V₃PO₁₀˙⁺ and V₄O₁₀˙⁺ with methane in a fast flow reactor under the same conditions are studied. A time of flight mass spectrometer is used to detect the cluster distribution before and after reactions. In addition to previously identified reaction of V₄O₁₀˙⁺ + CH₄ → V₄O₁₀H⁺ + CH₃˙, the observation of hydrogen atom pickup cluster V₃PO₁₀H⁺ suggests the reaction: V₃PO₁₀˙⁺ + CH₄ → V₃PO₁₀H⁺ + CH₃˙. The rate of the reaction of V₄O₁₀˙⁺ with CH₄ is approximately 2.5 times faster than that of V₃PO₁₀˙⁺ with CH₄. Density functional theory (DFT) calculations predict that structure of V₃PO₁₀˙⁺ is topologically similar to that of V₄O₁₀˙⁺, as well as that of P₄O₁₀˙⁺, which is very similar to V₄O₁₀˙⁺ in terms of methane activation in previous studies. The facile methane activation by the homo- and hetero-nuclear oxide clusters can all be attributed to the presence of an oxygen-centered radical (O˙) in these clusters. Further theoretical study indicates that the O˙ radical (or spin density of the cluster) can transfer within the high symmetry V₄O₁₀˙⁺ and P₄O₁₀˙⁺ clusters quite easily, and CH₄ molecule further enhances the rate of intra-cluster spin density transfer. In contrast, the intra-cluster spin density transfer within low symmetry V₃PO₁₀˙⁺ is thermodynamically forbidden. The experimentally observed reactivity difference is consistent with the theoretical consideration of the intra-cluster spin density transfer.