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Page 16 of 26 Yang et al. Soft Sci 2024;4:9 https://dx.doi.org/10.20517/ss.2023.43

shortcomings in achieving high resolution and high contrast intraoperative monitoring. With the increasing
demand for precise and conformal treatment of tumor cryoablation, developing intraoperative monitoring
means of high sensitivity and high resolution is of great significance in achieving accurate cryo-biomedicine.

As a multifunctional metallic material, gallium also shows a wide range of application prospects in
biological imaging and can realize a multi-mode imaging ability, including CT and magnetic resonance, and
[47]
it even shows powerful capability in the emerging photoacoustic imaging field . The characteristics of LMs
contribute greatly to imaging quality improvement. For example, LMs exhibit phenomenal X-ray
3
absorption and are greatly radiopaque due to their higher density (6.08 g/cm ) than aqueous solutions.
Gallium has been shown to be an excellent contrast agent for angiography, allowing even tiny capillaries to
[93]
be visualized at high resolution due to its fluidity and compliance . In tumor treatment, LMs can be
injected directly into tumor tissue, while the high fluidity enables the LMs to disperse rapidly at the targeted
tissue, providing complete and clear imaging of diseased tissues. In addition, LMs can also be injected
through blood vessels around tumors. It is well known that tumors induce a complex blood vessel network
to scramble for nutrients and oxygen. Fan et al. synthesized an injectable LM-calcium alginate hydrogel to
realize local embolization, which can not only cut off the energy supply for the tumor but also act as a
marker around the tumor for cryosurgery killing boundary localization . Plenty of studies have
[94]
demonstrated the imaging potential of LMs. However, the realization of high-quality intraoperative imaging
guidance mediated by LM remains to be further developed.

Aimed at the problem of incomplete killing caused by unclear imaging of tumor tissue during cryoablation
so far, efficient intraoperative imaging mediated by LMs is worthy of expectation. It is expected that LM-
mediated intraoperative imaging will provide potent medical guidance for the planning and ablation of
cryosurgery to achieve maximum tumor-killing efficiency and avoid tumor residuals and recurrence
[Figure 6A].

LM-mediated synergistic immune therapy
Adjuvant refers to a class of substances that can specifically bind to an antigen through physical or chemical
means to enhance the specific immunity of the antigen. In the past few decades, a variety of adjuvants have
been developed and applied in vaccine manufacturing successfully. Among these, aluminum, as one of the
most popular immune adjuvants, has been widely used in vaccine manufacturing and other fields since it
was first discovered by Glenny in 1926. Therefore, it is worth considering that gallium, as a congener of
aluminum, may also be an excellent immune adjuvant, as presented in Figure 6B.

Immunotherapy is a potential research direction for cancer treatment in the future , with the aid of tumor
[95]
vaccine to release the immunosuppressive state and stimulate the patient’s own immune system so as to
achieve the purpose of controlling and further eliminating the tumor. A key role of immune adjuvants in
tumor vaccines is to boost the uptake and cross-presentation of antigen-presenting cells . It is reported
[96]
that LM nanoparticle-based nano-vaccine can enhance antigen-presenting. Meanwhile, it can induce
moderate regional inflammation under infrared radiation, thus reinforcing the immune system response
and immune cell recruitment . The vaccine shows an evident suppression effect in mouse breast tumor
[97]
models and is thought to be highly adaptive for multi-type cancer treatment. However, the underlying
molecular mechanism of this study still needs to be further explored.

Compared with traditional surgical resection and chemoradiotherapy, cryoablation can retain the antigenic
activity of the tumor due to its cryogenic characteristics, which is crucial for relieving the
immunosuppression of middle and advanced tumors and effectively initiating the anti-tumor immune