Tumor-associated macrophages (TAMs) play a pivotal role in the progression and resistance of tumors to different anticancer drugs. TAMs can modulate the tumor microenvironment (TME) in favor of immune system exhaustion. The interactions of TAMs with TME can affect the function of cytotoxic CD8+ T lymphocytes (CTLs) and natural killer (NK) cells. Furthermore, TAMs can induce cancer cell proliferation by releasing some growth factors, such as transforming growth factor (TGF)-β. TAMs have several positive cross-talks with other immune suppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and cancer cells, leading to the release of growth factors, the proliferation of cancer cells and tumor growth. These interactions also can induce invasion and migration of cancer cells, angiogenesis, and metastasis. The inhibition of TAMs is an intriguing strategy for overcoming tumor resistance and suppression of cancer cells. Some natural-derived agents such as melatonin, curcumin, resveratrol, apigenin, and other flavonoids have shown the ability to modulate TME, including TAMs. These adjuvants may be able to boost antitumor immunity through the modulation of TAMs. This review explains the modulatory effects of some well-known naturally derived agents on the activity of TAMs. The modulation of TAMs by these agents may be useful in suppressing tumor growth and invasion.

Drug resistance is a hot topic issue in cancer research and therapy. Although cancer therapy including radiotherapy and anti‐cancer drugs can kill malignant cells within the tumor, cancer cells can develop a wide range of mechanisms to resist the toxic effects of anti‐cancer agents. Cancer cells may provide some mechanisms to resist oxidative stress and escape from apoptosis and attack by the immune system. Furthermore, cancer cells may resist senescence, pyroptosis, ferroptosis, necroptosis, and autophagic cell death by modulating several critical genes. The development of these mechanisms leads to resistance to anti‐cancer drugs and also radiotherapy. Resistance to therapy can increase mortality and reduce survival following cancer therapy. Thus, overcoming mechanisms of resistance to cell death in malignant cells can facilitate tumor elimination and increase the efficiency of anti‐cancer therapy. Natural‐derived molecules are intriguing agents that may be suggested to be used as an adjuvant in combination with other anticancer drugs or radiotherapy to sensitize cancer cells to therapy with at least side effects. This paper aims to review the potential of triptolide for inducing various types of cell death in cancer cells. We review the induction or resistance to different cell death mechanisms such as apoptosis, autophagic cell death, senescence, pyroptosis, ferroptosis, and necrosis following the administration of triptolide. We also review the safety and future perspectives for triptolide and its derivatives in experimental and human studies. The anticancer potential of triptolide and its derivatives may make them effective adjuvants for enhancing tumor suppression in combination with anticancer therapy.