The process of cancer metastasis consists of a long series of sequential and interrelated steps: tumor cells detach from the primary tumor, intravasate into the blood vessels or lymphatics, circulate in the body, adhere to vessel wall of distant organs, extravasate vessels, establish a new microenvironment and proliferate at the new site.2 It has been demonstrated that degradation of collagen in ECM can promote invasion and metastasis of cancer cells.29 With the malignant melanoma cells metastasizing into lung tissue, the ECM will be remodeled resulting in the transformation of density and distribution of collagen fibers,18,23,30 which leads to the SHGIR decrease as shown in Fig. 3. The reduction of MAFIR from day 3 to day 7 in Fig. 3 may be induced by the decrease of the normal cells in the tissue, which is also revealed by the HE images from day 3 to day 7. At the middle stage, the proliferation of cancer cells and imposing metabolic stress of the tissue—which are enhanced by the remodeled tissue structure, growth factors released by tissue stroma and no pressure from the surrounding microenvironment—lead to the MAFRI rising from day 10 to day 15.9,31 Eventually, unconstrained proliferation of cancer cell without migration results in large nodules within a “capsule” of ECM, which can induce the cell apoptosis due to the limited availability of nutrients and oxygen.9,32 It has been demonstrated that excessive proliferative signaling can also trigger cell senescence and/or apoptosis.33–35 In addition, the large nucleus of the cancer cell colonizing in the lung tissue cannot provide MAF, which is another reason of MAFRI reduction in later staged after day 18. According to the definition of MAFSI, the inflection point of each curve in Fig. 4 reveals that the density of collagen fibers at the depth of is much higher than that at any other depth. In Fig. 4(a)–4(c), the changes of MAFSIs versus time, especially in the tissue surface, are primarily induced by the cooperation of MAF and SHG intensity discussed above.