Biohacking the Tumour Microenvironment

Integrative Cancer Care. A Paradigm Shift

Cancer biology demands a paradigm shift from standard anticancer treatment to an integrative approach (Cheng et al., 2023). An evolving focus on integrative cancer involves shifting focus from the tumor to the environment surrounding the tumor, known as the tumor microenvironment [TME]. The TME is a complex network that contains not only tumor cells but also immune cells, and these immune cells can help to promote cancer growth, metastasis, and immune evasion (Baghban et al., 2020). Each type of cancer, possibly each tumor, has its unique TME. Take, for example, pancreatic ductal adenocarcinoma; this cancer is notorious for being undruggable and developing rapid chemotherapy resistance due to its unique TME (Murakami et al., 2019). Interestingly, many botanical medicines can remodel the TME (Dong et al., 2022), creating a novel integrative cancer care approach. The intense focus on the TME could be a critical factor in the potential for an integrative approach (Dong et al., 2022) to enhance existing therapeutics such as chemotherapy and immunotherapy.

The Role of the Tumour Microenvironment

It has been determined that cancer maintains its survival by manipulating and hijacking the immune cells present in the TME (Baghban et al., 2020). This can result in the common phenomenon of anticancer treatment resistance (Hirata & Sahai, 2017). Tumors are without oxygen and reside in an acidic environment, and this phenomenon triggers the TME to promote blood vessel supply to restore oxygen and give nutrients to the cancer (Anderson & Simon, 2020). This article will focus on tumor-associated macrophages [TAMs] and botanical medicine that can alter their role in the TME.

Tumour-Associated Macrophages and Botanical Medicine

TAMs are the immune cells most abundant within the TME (Zhou et al., 2020). A macrophage is part of the innate immune system, and its role is to eliminate damaged cells through programmed cell death (Hirayama et al., 2017). TAMs are derived from monocytes, which travel in the circulation; these monocytes are then recruited into the TME, where they become macrophages (Wu et al., 2020). Once recruited, these macrophages undergo polarization to either M1-like, which defends against cancer, or M2-like macrophages, which promotes cancer (Zhou et al., 2020). M1-like TAMs produce tumor-killing factors and are the leading force in the immune defense and suppression of tumors (Griess et al., 2020). The M2-like cells are a player in immunosuppression and resistance to anticancer drugs (Zhou et al., 2020). These macrophages can be found in any body tissue and are thought to be recruited during inflammation (Pan et al., 2020). The M1 and M2 macrophages have an extraordinary ability to change. They can be converted into each other within the tumor microenvironment due to environmental changes or response to anti-cancer treatment (Pan et al., 2020).

Botanical Medicines in Cancer Therapy

Current therapeutics do not specifically address the TME, and many early cancer trials are conducted on cancer cells that do not have a microenvironment. There is a pressing need to find immediately available substances that have potential to alter the TME, and several botanical medicines have been indicated for this application. Many current chemotherapeutic drugs have been derived from natural substances. For half a century, botanical medicine has been intensely studied in the hope of discovering new cancer therapies (Huang et al., 2021). Anti-cancer therapies originating from natural substances include vincristine, etoposide, irinotecan, and paclitaxel (Huang et al., 2021). Although an exciting prospect, developing natural products into drugs is a process abandoned mainly by pharmaceutical companies who now favor chemical synthesization to make pharmaceuticals (Huang et al., 2021).

Astragalus and Panax notoginseng: Potential in Cancer Care

Astragalus, a botanical medicine, has garnered intense interest due to its exciting and unique biological activities (Li et al., 2019). Astragalus has over 200 active compounds (Li et al., 2019) and boasts an excellent safety profile (Guo et al., 2018). Regarding macrophages in the TME, animal studies confirm that M2-like macrophages decrease with Astragalus, leading to reduced cell invasion, metastasis, and blood vessel formation (Xu et al., 2018). M1-like macrophages, which enhance the killing of tumors have been shown to become upregulated with the use of Astragalus (Wei et al., 2019), and this could be due to the repolarisation of macrophages from the M2-like subtype to M1-like subtype (Liu et al., 2020). Animal studies by Liu et al. (2020) demonstrated that along with tumor reduction, there is an increase in M1-like macrophages and a decrease in M2-like subtype. Astragalus has been shown to reverse immunosuppression in cancer and reduce the inflammatory nature of the TME (Li et al., 2020).

Many studies have documented the synergistic effects of Astragalus when given as an adjunct to standard chemotherapy; in animal studies undertaken by Chu et al. (2019), it was demonstrated that Astragalus increased the metabolic effect of Gemcitabine, which is standard chemotherapy used in pancreatic cancer. In animal studies by Cheng et al. (2021), the overall tumor response rate in gastric cancer was improved with the combination of Astragalus and platinum-based chemotherapy. In a meta-analysis by Lin et al. (2019), four studies that tested the effects of Astragalus as an adjunct to chemotherapy found a significant improvement in tumor response rate. In cervical cancer, the combination of Astragalus and chemotherapy improved tumor response rate and reduced side effects from chemotherapy. Wang et al. (2016) demonstrated increased tumor response rate and significant overall survival when Astragalus was combined with platinum-based chemotherapy in non-small cell lung cancer.

Panax notoginseng is a Chinese botanical containing ginsenoside, the primary active component (Zhang et al., 2019). Ginsenosides can induce cancer cell death by interfering with metabolic pathways and disrupting the tumor cell cycle (Li et al., 2020). Ginseng is a potential botanical for counteracting the immunosuppressive TME as it modulates cell differentiation to restore lethality to cancer cells (Li et al., 2021). Ginsenosides can convert M2-like macrophages into M1-like macrophages, restoring the anti-tumor effect within the TME (Li et al., 2018). Regarding affecting blood vessel growth for cancer, ginsenosides inhibit cells responsible for driving this growth (Kim et al., 2021), which is induced by the TME low oxygen environment (Li & Qu, 2019).

Conclusion – Embracing Botanical Medicine in Cancer Treatment

Considering botanical medicine as an adjunct therapy should be considered in patients who have a cancer diagnosis. This article has focused on a narrow theme; however, astragalus and Panax ginseng have shown many other benefits in cancer, significantly mitigating unwanted side effects from chemotherapy.

PLEASE NOTE:Natural medicine carries risks if not prescribed by a qualified practitioner familiar with oncology, chemotherapy, and their interactions.